Patent Docs

In re Packard (Fed. Cir. 2014)

May 18, 2014

By Kevin E. Noonan —

Oft times it appears that, serendipitously or by design, the Federal Circuit issues an opinion on an aspect of patent law that the Supreme Court is also considering. And sometimes the shadow of the Court's impending decision, like an unobserved new planet or dark star bends the appellate court's decisions in ways consistent with the likely view of the law expected to issue from the Court (because the Supreme Court rarely grants certiorari in an appeal from a Federal Circuit decision just to affirm). In its decision in the Packard case, the Federal Circuit takes a different tack, relying on the differences in how a claim's compliance with the patent statute's indefiniteness standard is assessed during prosecution compared with the "insolubly ambiguous" standard now under Supreme Court review in Nautilus v. Biosig. Incredibly, the panel asserts that the Court has never addressed this question of the proper pre-issuance indefiniteness standard that the Patent Office should apply.

The case arose as an appeal from the Patent Trial and Appeal Board's affirmance of the Examiner's final rejection for indefiniteness of the claims of Mr. Packard's patent application directed towards a coin change holder illustrated by Figures 1 and 2 from the application:

Claims 28, 29 and 34 were declared to be representative in the opinion:

28. I claim a small, thin, flat plane, rectangular change holding card and wallet/billfold or purse construction with the front top side of the card comprising three raised, straight, parallel, double flanged separators and two raised, straight, parallel, double flanged side edges and a raised side edge end thereby forming four parallel, side by side, flanged coin holding channels or rows of the same length and of different widths, one for quarters, one for dimes, one for nickels, and one for pennies, that are similarly blocked at one side edge by the raised side end edge with the other side of the channel/rows open except for small, fixed, flexible, partially moveable, rubber or plastic retainers that are attached to the topside and ends of the double flanged separators such that coins can be retained on the card and yet slide freely above the surface of the card and obliquely overlap as necessary within the channel/rows between the separators while the bottom, back side of the card is constructed with a wallet, billfold or purse extending from it.

29. The change holding card wallet, billfold, purse of claim 28, wherein the change holding card is constructed as part of the wallet, billfold, or purse and affixed to a surface and contained within the wallet, billfold or purse.

34. I claim a small thin uniformly flat plane rectangular coin holding card [c]omprising side edge retainers, a closed side retainer, small inclined/sloped end protrusions, multiple raised parallel, straight and double flanged channel/row separators, small flexible protruding retainers on the top side ends of the channel/row separators, all of which are arranged on the upper surface of the card such that a various denomination of coins can be held and retained on the card within a respective channel/row and can slide freely within the double flanges and slightly above the flat surface of the card and can also be stored obliquely partially overlapping.

The Examiner's rejections were based on the following terms, and the corresponding contrary rationales between the Applicant and the Office:

During prosecution the applicant refused to further disclose the meaning of these terms or their bases, and as a result the Examiner maintained her rejection that these terms were indefinite for being (merely) "unclear," pursuant to the Manual of Patent Examining Procedure (MPEP) § 2173.05(e). Before the Federal Circuit, as he had before the Board, the applicant maintained that the proper basis for rejecting claims under 35 U.S.C. § 112(b) was to apply the Federal Circuit's "insolubly ambiguous" standard, and further argued that under this standard if any meaning can be ascribed to the term(s) then the Office could not maintain an indefiniteness rejection.

The Federal Circuit disagreed, affirming the Patent Office's grounds of rejection in a per curiam opinion by a panel including Judges Plager, O'Malley, and Taranto. The panel cited the statutory provisions relating to what it termed "the USPTO's examination function (35 U.S.C. § 131) in applying the substantive law under § 112(b). As stated in Keystone Bridge Co. v. Phoenix Iron Co., 95 U.S. 274, 278 (1877), an applicant's "claim is, or is supposed to be, examined, scrutinized, limited, and made to conform to what he is entitled to" by the Office. Under prevailing Patent Office procedure, the process is iterative between the Office and an applicant, wherein the Office identifies deficiencies and failures to satisfy the statutory requirements of patentability in claims it examines and the applicant has the opportunity to amend, argue, or both in response. The panel noted that the Court has expressly approved this "procedural mechanism" in In re Piasecki, 745 F.2d 1468 (Fed. Cir. 1984), placing the initial burden of rejection (establishing a prima facie case) on the Office (through its examiners). That procedural approach is appropriate here, according to the Court.

In reviewing the question of indefiniteness, the panel noted that the basis for indefiniteness rejections during prosecution differ from the grounds that can be asserted after a patent has granted, citing Exxon Research & Eng'g v. United States, 265 F.3d 1370, 1380 (Fed. Cir. 2001). As a policy matter this makes sense, in the panel's view, due to the differences between the two circumstances (inter alia, the presumption of validity and the clear and convincing evidence standard for invalidating a granted claim, and without any consideration for the litigation standard — the Court referencing that standard being under review in Nautilus, Inc. v. Biosig Instruments, Inc., 715 F.3d 891 (Fed. Cir. 2013), cert. granted, 82U.S.L.W. 3195 (U.S. Jan. 10, 2014) (No. 13-369)). This policy also protects the public interest, requiring a patentee to "notify the public of what is within the protections of the patent, and what is not," citing Merrill v. Yeomans, 94 U.S. 568, 573-74 (1876); and United Carbon Co. v. Binney & Smith Co., 317 U.S. 228, 236 (1942). But the panel noted the requirement does not compel claim language that operates with "mathematical precision" but rather is tailored to the claimed subject matter, citing Georgia-Pacific Corp. v. U.S. Plywood Corp., 258 F.2d 124, 136 (2d Cir. 1958) for this principle.

The panel also places the responsibility for claims lacking the statutorily required clarity on the applicant, stating that "[g]iven the role of the applicant in the process, it is a reasonable implementation of the examination responsibility, as applied to § 112(b), for the USPTO, upon providing the applicant a well-grounded identification of clarity problems, to demand persuasive responses on pain of rejection." "That approach decides this case," according to the panel, "because Mr. Packard did not offer a satisfactory response to well-grounded indefiniteness rejections in this case." And:

In some cases it is difficult enough for courts to construe claims when the draftsperson has made every effort to be clear and concise, let alone when the claims have readily observable ambiguities or incoherencies within them. Because Mr. Packard had an opportunity to bring clarity to his claim language, we affirm the Board's findings as to indefiniteness under the MPEP standard properly applied by the USPTO, the standard which we have here approved.

Judge Plager wrote separately because his view is that "a petitioner to this court seeking reversal of a decision is entitled to an explanation of why the arguments on which he relied for his appeal did not prevail" (and he believed that the per curiam opinion did not directly address the "significant" issues Mr. Packard raised). These involve the proper standards for indefiniteness, which Judge Plager writes the Supreme Court has considered "[a]s far back as 1853 in Brooks v. Fiske, 56 U.S. 212 (1853)" and concluded that "the overriding policy considerations [are] that claims must unambiguously define any invention over the prior art, and provide notice to the public." These considerations have been consistently applied by the Court, Judge Plager citing White v. Dunbar, 119 U.S. 47, 52 (1886), Merrill v. Yeomans, 94 U.S. 568, 570-74 (1887), Gen. Elec. Co. v. Wabash Appliance Corp., 304 U.S. 364, 372 (1938), and United Carbon Co. v. Binney & Smith Co., 317 U.S. 228, 236 (1942), in support of this proposition (as well as explicating all prior versions of the Patent Act back to 1836 as having the same requirements) ("throughout this history of patents, the statutory language regarding claim clarity remained largely unchanged, and indeed so did the understanding of what the statute requires").

Judge Plager also gets to the heart of Mr. Packard's argument, that the "insolubly ambiguous" standard for indefiniteness enunciated by the Federal Circuit in Exxon Research and Engineering Company v. United States, 265 F.3d 1371 (Fed. Cir. 2001), is the standard that must be applied by the Office during prosecution. That phrase, according to Judge Plager, was new, and the rest of the Federal Circuit's opinion hewed to the "traditional test for claim construction: whether the claims were so ambiguous that one of skill in the art could not reasonably understand their scope." Even this standard has not survived intact, according to Judge Plager, who cites the language from Datamize, LLC v. Plumtree Software, Inc., 417 F.3d. 1342,1347 (Fed. Cir. 2005), that "[s]ome objective standard must be provided in order to allow the public to determine the scope of the claimed invention." And to the extent that the "insolubly ambiguous" standard as "taken on a life of its own" it has also "generated considerable controversy (citing law review articles and blog posts).

But Judge Plager did not perceive it to be necessary to decide "whether the traditional test employed by courts for determining indefiniteness has or has not been modified or superseded by Exxon's 'insolubly ambiguous' phrase." Rather, he set forth the two types of difficulties in claim interpretation relevant to the definiteness question: whether a claim term is "incoherent" or whether it is ambiguous. The former results in a term that cannot be construed, because "there is no reasonably understandable meaning of the term in the context in which it appears." For such terms the skilled worker "cannot ascertain any reasonable meaning of the term as used" (emphasis in opinion). An ambiguous term, on the other hand, is just one that is subject to multiple reasonable meanings. This leads to the situation where there can be one of three choices in construing the term:

1) Give controlling weight to the policy of upholding the USPTO's decision to issue a presumptively valid patent, with substantially less concern for the notice function of patents.

2) Give weight to the notice function of patents, while still recognizing the role of the presumption of validity.

3) Give full weight to the importance of the notice function of patents, recognizing that it is the claim drafter/patentee who is ultimately responsible for problems created by ambiguous terms.

Judge Plager identifies the first of these options as being most consistent with the "insolubly ambiguous" standard. These considerations are used by courts post-issuance, according to Judge Plager; in contrast, the PTO's standard, as Judge Plager states it, is that ambiguity in claiming, whether intended or inadvertent, is not acceptable (a standard that comports most closely to the third option above). This standard "goes well beyond what this court is known to apply to claim interpretation when the issue is post-issuance compliance with § 112(b)" according to Judge Plager. But "it is within the authority of the USPTO to so interpret the applicable standard," in Judge Plager's view, and moreover "as a policy matter, [the Federal Circuit] should support the USPTO in so doing." Nothing in the statute precludes this application of the law by the Office, nor does any precedent from the Federal Circuit or the Court preclude the assertion of this standard. And cases such as In re Zletz, 863 F.2d 319 (Fed. Cir. 1989), and Halliburton Energy Servs., Inc. v. M-ILLC, 514 F.3d 1244, 1255 (Fed. Cir. 2008), "highlighted the important role that the USPTO, through its examination process, plays in ensuring the quality of patents and compliance with the statutory requirements." In summary:

In short, there are no legal obstacles to the USPTO's proposed interpretation, and there are compelling reasons why, as a policy matter, this court should not preclude or otherwise interfere with the USPTO carrying out its full responsibilities under the Patent Act. Further, there is no reason why those trained and employed in the art of patent and patent claim drafting cannot comply with the USPTO requirements, recognizing that the nature of the invention and the particular art involved will affect the degree to which precision in language is possible.

Any efforts to improve the quality and clarity of patent claims should be encouraged, according to Judge Plager, who takes the time (in a portion of the opinion that illustrates how significantly the zeitgeist against patents has turned) to set forth a litany of "good reasons why unnecessary incoherence and ambiguity in claim constructions should be disapproved (citing many from the academy and other commentators critical of the patent system):

• they generate many of the claim construction disputes that plague the courts;

• they increase the cost to the society of new products and ideas. As one study put it, "[l]ow quality patents are those that protect inventions of limited novelty or that provide overly broad protection . . . ,which can be costly to society," citing Patents and Innovation: Trends and Policy Challenges, OECD, 28 (2004);

• they inhibit the opportunity for design-arounds and legitimate competition. A Federal Trade Commission Study observed that an overly broad patent "can block competition . . . and harm innovation," Federal Trade Commission, To Promote Innovation: The Proper Balance of Competition and Patent Law and Policy, A Report by the Federal Trade Commission, at 3 (October 2003);

• and they waste scarce judicial resources on claim construction cases that should never have been necessary to litigate, supporting and encouraging the kinds of litigation that have made "patent trolls" dirty words. (Patent trolls are also known by a variety of other names: "patent assertion entities" (PAEs), "non-practicing entities" (NPEs).

In re Packard (Fed. Cir. 2014)
Panel: Circuit Judges O'Malley, Plager, and Taranto
Per curiam opinion
Court Report

May 18, 2014

By Sherri Oslick —

About Court Report: Each week we will report briefly on recently filed biotech and pharma cases.

Alza Corp. et al. v. Mylan Pharmaceuticals Inc. et al.
1:14-cv-00085; filed May 15, 2014 in the Northern District of West Virginia

• Plaintiffs: Alza Corp.; Janssen Pharmaceuticals, Inc.
• Defendants: Mylan Pharmaceuticals Inc.; Mylan Inc.

Alza Corp. et al. v. Mylan Pharmaceuticals Inc. et al.
1:14-cv-00594; filed May 12, 2014 in the District Court of Delaware

• Plaintiffs: Alza Corp.; Janssen Pharmaceuticals Inc.
• Defendants: Mylan Pharmaceuticals Inc.; Mylan Inc.

The complaints in these cases are substantially identical. Infringement of U.S. Patent No. 8,163,798 ("Methods and Devices for Providing Prolonged Drug Therapy," issued April 24, 2012) following a Paragraph IV certification as part of Mylan's filing of an ANDA to manufacture a generic version of Alza's Concerta® (methylphenidate hydrochloride, used to treat attention deficit hyperactivity disorder). View the Mylan complaint here.

Cephalon Inc. v. InnoPharma Inc.
1:14-cv-00590; filed May 9, 2014 in the District Court of Delaware

Infringement of U.S. Patent No. 8,609,863 ("Bendamustine Pharmaceutical Compositions," issued December 17, 2013) following a Paragraph IV certification as part of InnoPharma's filing of an ANDA to manufacture a generic version of Cephalon's Treanda® (bendamustine hydrochloride, used to treat chronic lymphocytic leukemia and non-Hodgkin's lymphoma). View the complaint here.

Otsuka Pharmaceutical Co. v. Alembic Pharmaceuticals Ltd. et al.
1:14-cv-02982; filed May 9, 2014 in the District Court of New Jersey

• Plaintiff: Otsuka Pharmaceutical Co.
• Defendants: Alembic Pharmaceuticals Ltd.; Alembic Ltd.; Alembic Global Holding SA; Alembic Pharmaceuticals Inc.

Infringement of U.S. Patent Nos. 8,017,615 ("Low Hygroscopic Aripiprazole Drug Substance and Process for the Preparation Thereof," issued September 13, 2011), 8,580,796 (same title, issued November 12, 2013), 8,642,760 (same title, issued February 4, 2014), and 8,518,421 ("Flashmelt Oral Dosage Formulation," issued August 27, 2013) following a Paragraph IV certification as part of Alembic's filing of an ANDA to manufacture a generic version of Otsuka's Abilify® (aripiprazole, used to treat bipolar disorder and schizophrenia). View the complaint here.
Conference & CLE Calendar

May 18, 2014

May 22, 2014 – "Patent Infringement: Structuring Opinions of Counsel: Leveraging Opinion Letters to Reduce the Risks of Liability and Enhanced Damages" (Strafford) – 1:00 to 2:30 pm (EDT)

May 22, 2014 – "Amending Claims: Assessing the Options Right Now at the USPTO" (Intellectual Property Owners Association) – 2:00 to 3:00 pm (ET)

June 4, 2014 – "Patent Due Diligence Post-AIA: Avoiding Dangers of Inadequate Investigation — Evaluating Validity of Key Patents, Identifying Enforceability Issues, Addressing New Considerations Under the AIA" (Strafford) – 1:00 to 2:30 pm (EDT)

June 4-6, 2014 – Biosimilars*** (American Conference Institute) – New York, NY

June 9-10, 2014 – Hatch-Waxman Boot Camp*** (American Conference Institute) – Chicago, IL

June 10, 2014 – "'Standing Out' — The Supreme Court's Redefined Standard for Fee Shifting in Patent Litigation, and How It Might Impact 'Patent Troll' Litigation" (McDonnell Boehnen Hulbert & Berghoff LLP) – 10:00 am to 11:15 am (CT)

June 10, 2014 – "Patent Dispute Resolution at the ITC and PTAB: Alternatives to District Court Litigation" (American Bar Association (ABA) Center for Professional Development, Section of Intellectual Property Law, and Young Lawyers Division) – 1:00 to 2:30 pm (ET)

June 11-13, 2014 – Fundamentals of Patent Prosecution 2014: A Boot Camp for Claim Drafting & Amendment Writing (Practising Law Institute) – New York, NY

June 19, 2014 – "Double Patenting: Defeating Double Patenting Rejections and Avoiding Terminal Disclaimer" (Strafford) – 1:00 to 2:30 pm (EDT)

June 23-26, 2014 – BIO International Convention (Biotechnology Industry Organization) – San Diego, CA

June 25-26, 2014 – International Forum on Pharma Patent Extensions*** (C5) – London, England

July 9-11, 2014 – Fundamentals of Patent Prosecution 2014: A Boot Camp for Claim Drafting & Amendment Writing (Practising Law Institute) – San Francisco, CA

July 20-22, 2014 – 2014 Annual Meeting & Conference (National Association of Patent Practitioners) – Alexandria, Virginia.

August 13-15, 2014 – Advanced Patent Law Seminars (Chisum Patent Academy) - Seattle, WA

August 18-20, 2014 – Advanced Patent Law Seminars (Chisum Patent Academy) - Seattle, WA

***Patent Docs is a media partner of this conference or CLE
NAPP Annual Meeting

May 16, 2014

The National Association of Patent Practitioners (NAPP) will be holding its 2014 Annual Meeting & Conference on July 20-22, 2014 in Alexandria, Virginia. A "Nuts & Bolts" short-course will be offered on July 20. Topics to be covered during the short course include:

• Do-It-Yourself Patent Searching
• Patent Application Preparation
• Responding to an Office Action
• Arguing Against Combining References
• Client Counseling: Setting Realistic Expectations
• Roadmap for Drafting a Design Application (It's Different!)

Topics to be discussed during the July 21-22 conference will include:

• "USPTO Day"
• Our Changing Practice: Decisions from the Federal Court
• Best Practices: Minimizing the Risk of Malpractice
• On Your Radar: Docketing Systems Reviewed
• Covering All Bases: PCT Considerations
• Game-Changers: Design Patent Case Studies
• Client Counseling: Licensing, Monetizing and Alternatives to Patents

A program for the meeting can be found here.

The registration fee for the short-course is $495 (for NAPP members) or $695 (for non-members). The registration fee for the annual meeting and conference is $795 (for NAPP members) or $995 (for non-members). The above rates are in effect until June 15. Those interested in registering for the meeting can do so here.
IPO Webinar on Amending Claims in IPR Proceedings

May 16, 2014

The Intellectual Property Owners Association (IPO) will offer a one-hour webinar on "Amending Claims: Assessing the Options Right Now at the USPTO" on May 22, 2014 beginning at 2:00 pm (ET). A panel consisting of Scott McKeown of Oblon Spivak McClelland Maier & Neustadt, PC; Lissi Mojica of Dentons US LLP; and Karl Renner of Fish & Richardson, PC will examine all the options for amending claims available at the USPTO in light of the most recent decisions of the PTAB and the USPTO’s Central Reexamination Unit (CRU).

The registration fee for the webinar is $130 (government and academic rates are available upon request). Those interested in registering for the webinar can do so here.
Webinar on Defeating Double Patenting Rejections

May 16, 2014

Strafford will be offering a webinar/teleconference entitled "Double Patenting: Defeating Double Patenting Rejections and Avoiding Terminal Disclaimer" on June 19, 2014 from 1:00 to 2:30 pm (EDT). Thomas L. Irving of Finnegan Henderson Farabow Garrett & Dunner; Donna M. Meuth, Associate General Counsel – Intellectual Property for Eisai; and Margaret J. Sampson of Vinson & Elkins will provide guidance to IP counsel for understanding B delay possibilities and double patenting, and will analyze recent court treatment and offer best practices to defeat double patenting rejections and avoid terminal disclaimers. The webinar will review the following questions:

• What is the scope of double patenting?
• What is the examiner's duty for rejecting double patents?
• What steps can be taken to defeat double patenting rejections?
• What best practices can be employed to avoid terminal disclaimers?

The registration fee for the webinar is $297 ($362 for registration and CLE processing). Those registering by May 23, 2014 will receive a $50 discount. Those interested in registering for the webinar, can do so here.
Pharma Patent Extensions Conference

May 16, 2014

C5 (UK) will be holding its 13th International Forum on Pharma Patent Extensions on June 25-26, 2014 in London, England. The conference will provide optimal strategies to help attendees maximize their patent portfolios, including:

• The radical SPC decisions in Georgetown University, Actavis and Eli Lilly;
• Capitalise on second medical use patents by implementing proven strategies and utilising tactical enforcement and remedial methods;
• Fundamental update on the imminent Unitary Patent and Unified Patent Court and how to adapt business strategies effectively;
• The 'Right' to Priority case law developments and their implications for patents;
• Expand patent portfolios by taking advantage of the latest patent expiry strategies;
• A cross jurisdiction analysis of the Bolar exemption and how to operate the recent developments advantageously;
• Essential insight into personalised medicines and the consequences of recent case law;
• Recent developments in U.S. patent reform and its impact on global patent management strategies; and
• Hear key insights into biosimilars and the opportunities to obtain market and commercial opportunities.

In particular, C5 faculty will offer presentations on the following topics:

• How the Latest Landmark SPC Decisions Will Impact Your Patents Life Cycle
• A Critical Time for the Bolar Exemption — How, When and Where Does it Apply?
• Understand the Value of Second Medical Use Patents: An Analysis of Strategies and Enforcement
• The 'Right' to Priority — Pitfalls vs. Benefits
• Patently Dangerous: Strategic Patent Use and Competition Law Enforcement
• A Crucial Update on Patent Term Adjustments and Extensions in the United States
• The Final Countdown — The Unitary Patent and Unified Patent Court (UPC): Ensuring You Are Ready
• Expanding Your Patent Profile for Personalised Medicines
• How the Latest Developments in India are Affecting the Pharma Patent Landscape
• Assessing the Market Opportunities and Commercial Practicalities of Biosimilars for Pharma Companies
• Capitalise on the Latest Patent Expiry Tactics

An early riser workshop, entitled "How to Improve Your Patent Portfolio with the Latest Successful Patent Filing Strategies," will be offered from 8:00 to 10:00 am on June 26, 2014.

A complete brochure for this conference, including an agenda, list of speakers, detailed descriptions of conference sessions, and registration form can be downloaded here.

The registration fee is £1795 (conference alone), £2295 (conference and workshop). A webcast of the conference is being offered for £745. Those registering by May 23, 2014 will receive a £100 discount off the live conference/workshops or a £200 discount off the webcast. Those interested in registering for the conference can do so here, by calling +44 20 7878 6888, by faxing a registration form to +44 20 7878 6885, or by e-mailing registrations@C5-Online.com.

Patent Docs is a media partner of C5's Pharma Patent Extensions conference.
USPTO Holds Forum on Subject Matter Eligibility — Part III

May 15, 2014

By Donald Zuhn —

Last Friday, the U.S. Patent and Trademark Office held a four-hour long forum to receive public feedback on the Myriad-Mayo Guidance, which was issued by the Office on March 4. According to the Office's Guidance webpage, the forum was intended to provide an opportunity for stakeholders to present their interpretation of the impact of Supreme Court precedent on the complex legal and technical issues involved in subject matter eligibility analyses during patent examination.

On Monday, we reported on the opening remarks provided by Drew Hirshfeld, Deputy Commissioner for Patent Examination Policy, and the overview of the Guidance provided by Raul Tamayo, Senior Legal Advisor for the Office of Patent Legal Administration. Yesterday, we reported on the first of three groups of public presentations. Today, we report on the second group of public presentations. This group of presenters consisted of Courtenay C. Brinckerhoff of Foley & Lardner LLP; Dr. Leslie Fischer of Novartis Pharmaceuticals Corp.; and Dr. Warren D. Woessner of Schwegman Lundberg & Woessner, P.A.

Like prior presenters Dr. Sauer and Dr. Sonnenfeld, Ms. Brinckerhoff (at left) began her presentation by contending that the Guidance "[e]xtends Myriad to subject matter that was not before the Court and/or that the Court expressly stated that it was not addressing," including for example, compositions of matter, methods of treatment, and methods of manufacture. Noting that the Supreme Court in Myriad and Mayo "warned against overly-broad applications of the subject matter eligibility exceptions [because] too broad an interpretation of this exclusionary principle could eviscerate patent law," Ms. Brinckerhoff declared that the Guidance "threatens to do just that — eviscerate patent law and stifle investment and innovation." In support of her argument, she cited a Managing Intellectual Property article by Sherry Knowles that relied on a Journal of Natural Products paper by Dr. David J. Newman and Dr. Gordon M. Cragg entitled "Natural Products as Sources of New Drugs over the 30 Years from 1981 to 2010," (see "Sherry Knowles 'Speaks Truth to Power' on the PTO's § 101 Guidelines"). As shown in a slide from Ms. Brinckerhoff's presentation, 71% of the 1,355 drugs approved between 1981 and 2010 would fall outside the scope of the Guidance.

According to Ms. Brinckerhoff, the Office erred in two respects when crafting the Guidance. In particular, she argued that the Office relied on an overly narrow interpretation of Funk Bros. that resulted in an overly broad application of that case, and the Office parsed claim elements rather than considering claims as a whole. With respect to the Office's interpretation of Funk Bros., Ms. Brinckerhoff explained that the Guidance finds a composition comprising a combination of components to be non-eligible unless at least one of the components is not a natural product (as in the training slides example of pomelo juice) or unless the components have a specific physical interrelationship (as in the Guidance's firework example).

Pointing to a passage from Funk Bros. (see slide below), Ms. Brinckerhoff remarked that while she sees "mention after mention of function and utility" in the citation, the Office instead "sees that same passage as requiring a markedly different structure." Ms. Brinckerhoff also reminded the Office (as did a number of presenters) that Chakrabarty spoke of "markedly different characteristics," and not "markedly different structure."

Contending that the Supreme Court did not question the eligibility of pharmaceutical compositions in either Myriad or Mayo, Ms. Brinckerhoff suggested an alternative test for compositions based on a proper reading of Funk Bros. (as set forth in the following slide from her presentation).

Ms. Brinckerhoff next inquired as to why method of treatment claims were subject to eligibility scrutiny as neither Mayo nor Myriad undermined the eligibility of such claims, and she indicated that she didn't understand why these types of claims were being rejected by examiners. She concluded her presentation by noting that applicants had few options for dealing with the Guidance. She asked whether applicants would need to take every adverse case to the Patent Trial and Appeal Board, and because the appeal route could take 3-5 years, inquired as to whether the Office would offer an expedited route to get a PTAB decision.

A copy of Ms. Brinckerhoff's presentation can be found here.

The second presenter, Dr. Leslie Fischer (at right), argued that the problem with the Guidance was that no consideration is given to the function of claimed subject matter. Instead, "subject matter comprising only natural products must have a marked structural difference from the corresponding natural product in order to be patent eligible" (emphasis in presentation). According to Dr. Fischer, the solution would be to use the following test for patent eligibility:

Whether the claimed subject matter, as a whole, has:
(1) a physical difference (e.g., structure, form, purity, etc.) relative to the natural product(s); and
(2) a different function or use relative to the natural product(s).

Dr. Fischer also noted that the Office's "web" of relevant cases (as shown in a slide from Mr. Tamayo's presentation) overlooked a few important decisions (which she indicated in her revised web). These additional cases "tell us that function is important."

According to Dr. Fischer, the tariff cases Hartranft v. Wiegmann, 121 U.S. 609 (1877), and Lawrence v. Allen, 48 U.S. 785 (1849), indicate that a manufacture requires a new or distinctive form, character, name, or use. Noting that Chakrabarty cites Hartranft in finding that the claimed bacteria in that case constituted "a product of human ingenuity 'having a distinctive name, character [and] use,'" Dr. Fischer concluded that "[t]he consideration of functional changes as relevant to patent eligibility is in accordance with historical tar[]iff and patent cases, which consider whether products derived from nature have different functions and uses" (emphasis in presentation). Dr. Fischer also noted that the Myriad Court discussed Chakrabarty (and that case's citation to Hartranft) and Funk Bros. in similar terms, and concluded that "Myriad's use of Chakrabarty and Funk is perfectly compatible with considering whether a functional change can convert an otherwise 'natural product' into patent eligible subject matter." Thus, she declared that "Myriad does not tell us to throw away function."

Dr. Fischer further suggested that Myriad's claims were not directed to discrete chemical compositions, but rather were directed to information. She explained that the Myriad Court entwined DNA's functional aspect (i.e., information) with DNA's molecular structure (i.e., structure). In her view, "Myriad addresses a product, that, according to the Court, does not have a different function or structure from that which is found in nature." Dr. Fischer contended that the Myriad Court saw the characteristics of structure (sequence) and function (information) as inseparable, and argued that "Myriad has very limited applicability — [applying] only to subject matter in which molecular structure and function completely collapse, e.g., DNA." Dr. Fischer concluded her presentation by asking why the Office had decided to use the most damaging interpretation of Myriad, when it did not have to, and by reminding the Office that "for natural products, function matters."

A copy of Dr. Fischer's presentation can be found here.

Noting that the Guidance "require[s] both that the claimed compound be 'non‐naturally occurring' and 'markedly different in structure from naturally occurring products' to be patent‐eligible," the final presenter in the second group, Dr. Woessner (at left), pointed out that "[n]either Myriad, Mayo nor Funk Bros. define 'natural product', much less a 'markedly structurally different, non‐naturally occurring product.'" Dr. Woessner next reminded forum attendees that while the Supreme Court vacated In re Bergy, 596 F.2d 952 (CCPA 1979) (finding pure culture of bacterium producing antibiotic not to be a natural product) when it took up Chakrabarty, Bergy has nevertheless been extensively cited as precedent ever since.

Noting that Chakrabarty contains no language disparaging Bergy or requiring structural alterations, Dr. Woessner contended that the claimed subject matter of Bergy would satisfy the test in Chakrabarty. Dr. Woessner concluded his presentation by declaring that neither Myriad nor Mayo provide a sufficient rationale for departing from about a century of practice that culminated in Bergy. According to Dr. Woessner, the Guidance has been "disruptive, regressive and should be withdrawn." He also reminded the Office that the first version of the written description guidelines were "taken back for a major overhaul after a public outcry just like this."

A copy of Dr. Woessner's presentation can be found here.

Before moving on to the third group of presentations, representatives from the Office fielded questions and received additional comments from attendees. One attendee remarked that the Office had taken "a step backwards" and "gone way overboard" with the Guidance, and warned that "you will have your head handed to you" once the courts had a chance to consider the Guidance. Mr. Hirshfeld noted that the Office was "exploring" the structural versus functional issue that had been raised by a number of presenters, but pointed out that the Office could not ignore Funk Bros., which he believed constrained what the Office could do. Nevertheless, he asked attendees if there was "a way between Funk and Chakrabarty"? June Cohan, a Legal Advisor with the USPTO's Office of Patent Legal Administration who presented on the Guidance at the biotechnology/chemical/pharmaceutical (BCP) customer partnership meeting and at the BIO's 2014 Spring Intellectual Property Counsels Committee (IPCC) Conference, stated that she was particularly concerned about discerning function that is inherent from function that was "added" to the claimed subject matter by the applicant.

In the final post in this series, we will examine the comments made by the third group of public presenters as well as the open participation/question and answer session that concluded the forum.

For additional information regarding this topic, please see:

• "USPTO Holds Forum on Subject Matter Eligibility — Part II," May 14, 2014
• "Guest Post: How to Patent Grapefruit Juice — The New USPTO Guidance for Patent Eligible Subject Matter Is Both Sticky and Sour," May 13, 2014
• "USPTO Holds Forum on Subject Matter Eligibility — Part I," May 12, 2014
• "USPTO Tries to Address Public Misunderstandings Regarding Myriad-Mayo Guidance," April 16, 2014
• "USPTO Issues Guidance for Analyzing Subject Matter Eligibility of Claims Reciting Laws of Nature/Natural Principles, Natural Phenomena or Natural Products," March 4, 2014
USPTO Holds Forum on Subject Matter Eligibility — Part II

May 14, 2014

By Donald Zuhn —

Last Friday, the U.S. Patent and Trademark Office held a four-hour long forum to receive public feedback on the Myriad-Mayo Guidance, which was issued by the Office on March 4. According to the Office's Guidance webpage, the forum was intended to provide an opportunity for stakeholders to present their interpretation of the impact of Supreme Court precedent on the complex legal and technical issues involved in subject matter eligibility analyses during patent examination. On Monday, we reported on the opening remarks provided by Drew Hirshfeld, Deputy Commissioner for Patent Examination Policy, and the overview of the Guidance provided by Raul Tamayo, Senior Legal Advisor for the Office of Patent Legal Administration. Today, we report on the comments provided by several of the public presenters.

As we noted in Part I, the ten public presenters were divided into three groups, with each presenter being given 10 minutes to provide feedback on the Guidance. The first group of presenters consisted of Dr. Hans Sauer, Deputy General Counsel for Intellectual Property for the Biotechnology Industry Organization; Suzannah K. Sundby of Smith, Gambrell & Russell, LLP; Dr. Anthony D. Sabatelli of Dilworth IP LLC; and Dr. Kenneth H. Sonnenfeld of King & Spalding LLP.

Dr. Sauer (at left) began by noting that "BIO member companies operating in areas that have little or nothing to do with human genetics are beginning to receive 101 rejections of claims to pharmaceutical compositions, industrial enzymes, methods of treatment using medicinal molecules, and other inventions that were neither considered nor discussed in recent Supreme Court decisions." He pointed out that BIO members believe that in crafting the Guidance, "the PTO has gone beyond interpretation of recent Supreme Court decisions, and has engaged in unwarranted extrapolation and expansion of law, in ways not prompted by the Myriad decision." According to Dr. Sauer, notable examples of this expansion include "the application of a new 101 rationale to combination products," methods of drug administration or treatment, and "[t]he implicit but clear abandonment of cases like Parke‐Davis, In re Merz, In re Bergstrom, In re Kratz, and Merck v Olin Mathieson, which were briefed to the Supreme Court but neither discussed nor overruled."

Because "[t]he PTO is merely interpreting court decisions interpreting prior court decisions interpreting judicially‐created exceptions from the statute," Dr. Sauer contended that "the PTO is no better positioned to establish an authoritative interpretation of the Supreme Court’s 101 jurisprudence than are the lower courts." He added that:

Expanding Myriad's holding to all claims to isolated or purified natural molecules like antibiotics and other medicinal substances, and combinations thereof, and fermentation or distillation products or bacterial enzymes, will not only prospectively block inventors from acquiring commercially meaningful protection for products that were never even mentioned by the Supreme Court [but will] also cast[] a shadow over thousands of issued patents that the PTO now says would never be issued if they were examined today and — implicitly — should never have been issued in the first place.

Dr. Sauer also noted that "[t]he PTO's interpretation of the Supreme Court cases, as applied to biotech, is not the only permissible one," and then set forth a series of questions:

So what policy choice did the PTO make when it picked its current interpretation from all the different reasonable interpretations of these cases? Does the PTO believe the Supreme Court really meant to strike down claims to fungal antibiotics or industrial enzymes that go into laundry detergents? Does the PTO believe it is implementing the intent of Congress when it last passed Section 101? Or that a more draconian interpretation of Supreme Court pronouncements will advance the progress of the useful arts better than alternative readings?

As for answers to these questions, Dr. Sauer responded that "[w]e're left to guess, because that's a discussion we never had." He concluded his comments by declaring that:

There is no unified reading of Funk, Benson, Flook, Diehr, Chakrabarty, Pioneer, Bilski, Mayo, and Myriad that is fully coherent, free of internal tension, and that operates harmonically with the other requirements of patentability. We need the PTO to acknowledge that reality. And we need a dialogue not only over how to best interpret the caselaw we've been given, but also whether that caselaw leads us to the right place.

A copy of Dr. Sauer's written testimony can be found here.

The second presenter, Suzannah Sundby (at right), argued that there were three problems with the Guidance: (1) the factor-based approach set forth in the Guidance is inappropriate for § 101 eligibility determinations, (2) process and product claims should be evaluated using separate tests, and (3) the Office's interpretations of Mayo and Myriad in the Guidance are too broad. With respect to the first issue, Ms. Sundby indicated that "[a]n ineligible factor can negate an eligible factor," and as an example, pointed out that if the Guidance's weighing of factors approach was applied to the claims of Diehr, "the steps of installing the rubber in the press and the subsequent closing of the press would negate the fact that the process integrated the algorithm into a practical application, i.e., curing and molding rubber."

As for the second issue, Ms. Sundby contended that the test for process claims should be the "significantly more" standard of Mayo, and the test for product claims should be the "markedly different characteristic" standard of Chakrabarty. Moreover, as she pointed out "[n]owhere does the [Supreme] Court hold that a product must be both significantly more and markedly different."

In a theme repeated by many of the presenters, Ms. Sundby reminded the Office that the standard set forth in Chakrabarty was whether a naturally occurring product recited in a claim exhibits markedly different characteristics, and not whether that product exhibits markedly different structure. She argued that this markedly different characteristic could be either a structural difference or a functional one, and that this interpretation would be consistent with both Funk Bros. and Myriad, where the patent ineligible products at issue did not possess new, different, or changed characteristics.

With respect to the Office's interpretations of Mayo and Myriad in the Guidance, Ms. Sundby contended that "the PTO seems to interpret the 'apply it' discussion in Mayo as requiring unduly specific process steps," and that the Office "appears to interpret Myriad as applying to all things, isolated or synthesized, that can be derived from a product of nature." According to Ms. Sundby, the Supreme Court in Myriad "reasoned that information in the isolated DNA molecule is the same as it is in nature, and hence, the chemical changes resulting from its isolation did not result in a markedly different characteristic, e.g., change to the information." She concluded, therefore, that "Myriad does not stand for the rigid proposition that all compositions and molecules that originate from products of nature are patent ineligible" (emphasis in presentation). As a result of the Office's interpretation of Myriad, many therapeutic compositions will be found to be patent ineligible (as outlined in a slide from her presentation):

In concluding her presentation, Ms. Sundby suggested, inter alia, that the Office allow applicants of pending applications to switch elected inventions, make actual examples of claims and 101 analyses available to the public, and establish a procedure for reviewing eligibility determinations to ensure consistency and compact prosecution.

A copy of Ms. Sundby's presentation can be found here.

The next presenter in the group, Dr. Sabatelli (at left), began by focusing on the problems raised by the pomelo juice example in the Office's training slides and the Office's comments regarding the patent eligibility of gunpowder — a component of the claimed fountain-style firework of Example C in the Guidance. While acknowledging that there was a need for the Guidance and conceding that the Guidance was "an initial step in the right direction," he asserted that the Guidance was too complex and set forth too many factors (and suggested that more factors were likely to be added by the Office or the courts). He asked whether "we need[ed] a brighter, simpler line?" As for changes to the Guidance, Dr. Sabatelli asked the Office to provide more examples.

A copy of Dr. Sabatelli's presentation can be found here.

The final presenter in the first group, Dr. Sonnenfeld (at right), began his presentation by a showing a slide listing the claims of Example B of the Guidance:

Claim 1: Purified amazonic acid.

Claim 2: Purified 5-methyl amazonic acid.

Claim 3: A method of treating colon cancer, comprising: administering a daily dose of purified amazonic acid to a patient suffering from colon cancer for a period of time from 10 days to 20 days, wherein said daily dose comprises about 0.75 to about 1.25 teaspoons of amazonic acid.

He argued that Example B created gaps in the available protection for many biotech and pharmaceutical applicants. He noted, for example, that pharmaceutical composition claims (for which no exemplary claim was set forth in the Guidance) may be too narrow if a pharmaceutically acceptable carrier must impart a "significant difference," and that method of treatment claims could be limited to single indications and require the inclusion of multiple limiting elements. With respect to claim 1 of Example B, he asked whether the Office was analyzing the claim as a whole, and suggested that a claim to "amazonic acid" was different from a claim to "purified amazonic acid" (stating that purified amazonic acid does not exist in nature). In support for the patent eligibility of purified natural product claims, Dr. Sonnenfeld pointed to the Office's utility guidelines (as shown in the slide from his presentation):

And provided a list of patented purified natural product therapeutics:

Like Ms. Sundby, Dr. Sonnenfeld also argued that Myriad concerns genes and their information, and that the Myriad holding is limited to genes:

A copy of Dr. Sonnenfeld's presentation can be found here.

Before moving on to the second group of presentations, representatives from the Office fielded questions and received additional comments from attendees. One attendee remarked that the Guidance had been a "process failure" because the Office had neglected to include the community of practitioners sooner. In response, Mr. Hirshfeld stated that it was not the Office's intention to exclude the public from the discussion, but that the Office, in crafting the Guidance, was merely doing what it always had done with respect to the creation of examination guidelines. When Office representatives were asked by another attendee whether there was a Supreme Court case that said "markedly different" was the test for determining the eligibility of claims reciting natural products, Mr. Tamayo responded that the Office believed "Myriad focused us on that being the test." The forum then moved on to the second group of presenters.

In subsequent posts, we will examine the comments made by the remaining public presenters as well as the open participation/question and answer session that concluded the forum.

For additional information regarding this topic, please see:

• "Guest Post: How to Patent Grapefruit Juice — The New USPTO Guidance for Patent Eligible Subject Matter Is Both Sticky and Sour," May 13, 2014
• "USPTO Holds Forum on Subject Matter Eligibility — Part I," May 12, 2014
• "USPTO Tries to Address Public Misunderstandings Regarding Myriad-Mayo Guidance," April 16, 2014
• "USPTO Issues Guidance for Analyzing Subject Matter Eligibility of Claims Reciting Laws of Nature/Natural Principles, Natural Phenomena or Natural Products," March 4, 2014
FDA Releases Draft Guidance on Biosimilars

May 14, 2014

Sets Forth Clinical, Pharmacology Data Sufficient to Support Biosimilarity

By Kevin E. Noonan —

The Food and Drug Administration has released the first new Guidance relating to its evolving standards for satisfying the biosimilarity requirements of the Biologics Price Competition and Innovation Act (BPCIA) since its release in February 2012 of three basic Guidances that left many if not most of the relevant details unclear. This most recent Guidance is more specific, being directed particularly to the type and amount of clinical pharmacology data the Agency will require to demonstrate biosimilarity to a reference product but is expressly "being distributed for comment purposes only" and thus how the FDA will administer the BPCIA remains a work in progress.

The provisionality of the Guidance is acknowledged from the Introduction (Section I), where it is described as being antecedent to a Guidance "in its final form" that will be "one of a series" comprising how the Agency will implement the BPCIA. This Guidance "discusses some of the overarching concepts related to clinical pharmacology testing for biosimilar products, approaches for developing the appropriate clinical pharmacology database, and the utility of modeling and simulation for designing clinical trials."

The Guidance establishes (in Section II) the relevance of clinical pharmacological data to the question of biosimilarity, stating that "[c]linical pharmacology studies are normally a critical part of demonstrating biosimilarity by supporting a demonstration that there are no clinically meaningful differences between the proposed biosimilar and the reference product." These data are related to the "degree of similarity in drug exposure" between the reference drug product and the putative biosimilar. The Guidance also notes that such data typically include pharmacodynamics endpoints and pharmacometric analyses that can reveal "clinically meaningful differences," and thus "can add to the totality of the evidence, reduce residual uncertainty, and thus guide the need for and design of subsequent clinical testing to successfully support a demonstration of no clinically meaningful differences in the overall demonstration of biosimilarity." Which types of such studies are meaningful in any particular reference biologic product/biosimilar comparison will depend, inter alia, on the "residual uncertainties" remaining when all other types of comparison evidence are considered (e.g., structural, mechanistic and other physicochemical comparisons).

The Guidance sets forth "three key concepts" as being "especially relevant" to their assessment of the similarity of biosimilar products:

• Exposure and response assessment (Section III.A)
• Evaluation of residual uncertainty (Section III.B)
• Assumptions about analytical quality and similarity (Section III.C)

With regard to exposure and response assessment, the Guidance asserts that these data are "important for the determination of safety, purity, and potency of any biological product, as well as for the determination of any potential clinically meaningful difference between two products." But this assessment is "particularly challenging" in the biosimilar context, because what is being assessed is not a comparison between an active product that is a single molecule and its breakdown products but "a mixture of closely related, complex biological substances." The Guidance defines "exposure" to related to pharmacokinetic parameter, including dose, drug concentrations in blood, plasma and other biological fluids, and related variable including C_max, C_min , C_trough,ss, and area under the curve (AUC). Response, on the other hand, is defined in the Guidance as pharmacodynamics, "a direct measure of the pharmacological or toxicological effect of a drug," the assessment of which includes single or multiple biomarkers (where using "broader" biomarker panels are preferred if they "capture multiple pharmacological effects of the [biosimilar] product." In this regard, the Guidance cites "time of onset" of the marker relative to the combination of the time of onset, the "dynamic range" of the marker, how sensitive the marker is to differences between the reference drug and the biosimilar, relationships between changes in the marker and clinical outcomes, and the relevance of the marker on the mechanisms of action of the molecule.

The Guidance on evaluating residual uncertainty is less expansive, merely setting forth the FDA standard of assessing the "totality of the circumstances" on the evidence and suggesting that this evidence be collected and submitted "in a stepwise manner," including the PK and PD data "obtained in conjunction with clinical pharmacology studies."

Assumptions regarding analytical quality and similarity are defined in the context of such a "stepwise assessment of biosimilarity," wherein "extensive and robust comparative structural and functional studies (e.g. bioassays, binding assays, and studies of enzyme kinetics) should be performed to evaluate whether the proposed biosimilar product and the reference product are highly similar." This in turn depends on the state of the art regarding analytical assays, including those related to measuring molecular weight, post-translational modifications, heterogeneity, impurity and degradation profiles and functional properties of the biosimilar.

The differences between the reference drug product and biosimilar and the "type, nature, and extent" of those differences need to be supported by relevant information and experimental data, and if necessary additional data, and the Guidance explicitly notes that "certain differences in the results of the analytical characterization may preclude a determination by FDA that the proposed biosimilar product is highly similar to the reference product" and that, as a result the Agency will not approve the biosimilar application.

The Guidance also sets forth four different assessments decisions along a "developmental phase continuum":

• Not similar: Certain differences in the results of the analytical characterization may lead to an assessment of "not similar" and further development through the 351(k) regulatory pathway is not recommended unless, for example, modifications are made to the manufacturing process for the proposed biosimilar product that is likely to lead to a highly similar biological product.

• Similar: Further information is needed to determine if the product is highly similar to the reference product. Additional analytical data or other studies are necessary to determine if observed differences are within an acceptable range to consider the proposed biosimilar product to be highly similar to the reference product. As an example, glycosylation plays an important role in the PK of certain protein products. Manufacturing process conditions may impact glycosylation. Comparative PK and PD studies of the proposed biosimilar product and the reference product help resolve that some differences in glycosylation identified in the analytical studies would be within an acceptable range to consider the proposed biosimilar product to be highly similar to the reference product.

• Highly similar: The proposed biosimilar product meets the statutory standard for analytical similarity. The results of the comparative analytical characterization permit high confidence in the analytical similarity of the proposed biosimilar and the reference product, and it would be appropriate for the sponsor to conduct targeted and selective animal and/or clinical studies to resolve residual uncertainty and support a demonstration of biosimilarity.

• Highly similar with fingerprint-like similarity: The proposed biosimilar product meets the statutory standard for analytical similarity based on integrated, multi-parameter approaches that are extremely sensitive in identifying analytical differences. The results of these fingerprint-like analyses permit a very high level of confidence in the analytical similarity of the proposed biosimilar and the reference product, and it would be appropriate for the sponsor to use a more targeted and selective approach to conducting animal and/or clinical studies to resolve residual uncertainty and support a demonstration of biosimilarity.

The Guidance then sets forth a section (Section III.D) describing the "integrity" of the methods used in PK and PD studies (not surprisingly noting that these "should be accurate, precise, specific, sensitive, and reproducible"). These include (for PK studies) that the analytical method(s) used should be able to detect the active product and not just the total product in the formulation, and (for both PK and PD studies) that the assays chosen should be capable of providing the Agency with data that "are meaningful and reflective of drug exposure, the biological activity, and/or the PD effect of the proposed biosimilar product and the reference product." A rationale for the choice of assay and its relevance should also be provided. The Guidance then sets forth considerations regarding a number of specific assays, including:

• Ligand binding assays (differentiating between receptor/ligand and antibody/antigen binding assays);
• Concentration and activity assays (particularly with regard to enzyme replacement); and
• PD assays (noting that the measured activity "should be relevant to the clinical outcome").

With regard to safety and immunogenicity (Section III.E), the Guidance reiterates the caution from the earlier Guidances with regard to immune-mediated toxicity and the extent to which clinical pharmacologic data may be important to indicate differences requiring additional studies and appropriate study types, and that in certain circumstances the results of these studies may indicate that additional studies should not be pursued (because the differences are sufficient for the Agency to deny the biosimilar application). And the Guidance further cautions that, should the publicly available information on the reference drug product indicate a propensity for immune-mediated toxicity the biosimilar applicant should include assays "capable of detecting binding antibodies (and their neutralizing potential) [] in advance to analyze samples obtained from PK and PD studies, so that immunogenicity may be evaluated in real time" (the Guidance further references its prior FDA guidance for industry Bioanalytical Method Validation).

As it has in earlier Guidances, the Agency urges stakeholders to consult, especially with "critical study design issues," including crossover and parallel designs, which are of "particular relevance" (Section IV.A). The "preferred design" for PK similarity assessments, according to the Guidance, is a single-dose, randomized, crossover study, particularly with products having a "short" half-life (less than 5 days), "rapid" PD response ("onset, maximal effect, and disappearance in conjunction with drug exposure"), and multiple dosing regimes where "the PD effect is delayed or otherwise not parallel to the single-dose drug PK profile." Parallel study designs are recommended for biologic drugs having a long half-life and that elicit immunogenic responses. Regarding the reference drug product used in these studies (set forth in Section IV.B), the Agency states that "a sponsor may use a non-U.S. licensed comparator product in certain studies to support a demonstration that the proposed biological product is biosimilar to the U.S.-licensed reference product" but also should provide "adequate data or information to scientifically justify the relevance of these comparative data to an assessment of biosimilarity and to establish an acceptable bridge to the U.S.-licensed reference product." The type of "bridging data" the Agency will likely require can include structural and functional analytical data, and PK and PD study data comparing all three products (US reference drug product, non-US reference drug product, and biosimilar).

With regard to appropriate study populations (Section IV.C), the Guidance sets forth the pros and cons for each alternative (healthy volunteers vs. patients affected by the relevant disease or disorder) and the considerations that can be dispositive for the choice of population (generally, those that would provide data that is "the most informative for detecting and evaluating differences in PK and PD profiles between the proposed biosimilar product and the reference product"). Safety (with regard to healthy volunteers) and the possibility for immunogenicity or "known toxicity" (for affected patients) are noted as relevant considerations, and the Guidance also mentions the possible importance of demographics in instances where a particular patient demographic group would be "most likely to provide a sensitive measure of differences between the proposed biosimilar product and the reference product" (while requiring a biosimilar applicant to justify these choices). In other parts of the Guidance the Agency sets forth relevant considerations for dosing, which include (not surprisingly) a dose that is "most likely to provide clinically meaningful and interpretable data" (wherein the approved dose for the reference product being perhaps the right dose for studies involving affected patients). Alternative dose choices are also provided (see Section IV.D).

Other aspects of clinical pharmacologic studies set forth in the Guidance include route of administration (the same as the reference drug product; Section IV.E) and the types of pharmacokinetic (Section IV.F) and pharmacodynamics (Section IV.G) measurements that should be considered, as well as the "appropriate pharmacodynamics time profile" (Section IV.H) and statistics used for comparing PK and PD results from the biosimilar and reference drug product (Section IV.I).

The Guidance also contains a section (Section V) relating to "simulation tools" as part of study design and data analysis. The Guidance asserts that these tools can be useful in making many study choices set forth in earlier portions of the Guidance, and particularly notes the importance of making comparisons on the steep portion of a dose-response curve (which will more readily show differences between the biosimilar and the reference drug product) rather than in the "plateau" potion (which will not). The Guidance also suggests that a biosimilar applicant who does not have access to exposure-response data on the reference drug product can use such tools to produce a "small study to determine an optimally informative dose" or other alternatives.

The Guidance concludes with a reminder that the Agency has decided that it will assess biosimilarity between a putative biosimilar product and a reference drug product based on the totality of the evidence" (as set forth extensively in earlier Guidances).

One aspect of this Guidance, in addition to its (somewhat) greater specificity, is that what may constitute evidence that the biosimilar should not be approved is more explicitly recited (or at least that non-approval is an outcome dependent on evidence of differences between the reference drug product and the biosimilar). Generally, however, this Guidance provides an relatively small, specific, incremental advance in setting forth the Agency's course in providing a biosimilar approval pathway under the statute.

As set forth on the first page of the Guidance:

Comments and suggestions regarding this draft document should be submitted within 90 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register.

For questions regarding this draft document contact (CDER) Sandra Benton at 301-796-2500, or (CBER) Office of Communication, Outreach and Development at 1-800-835-4709 or 301-827-1800.

Copies of the Guidance can be found here.

Interested readers should take the Agency up on this offer; unlike other governmental Guidances, the FDA appears genuinely interested in working with its stakeholders to address their legitimate concerns regardinh how the Agency will administer the law.

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