UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`BEFORE THE PATENT TRIAL AND APPEALS BOARD
`
`
`SANOFI-AVENTIS U.S. LLC and
`SANOFI-AVENTIS DEUTSCHLAND GMBH
`Petitioners
`
`v.
`
`ASTRAZENECA PHARMACUTICALS LP and
`AMYLIN PHARMACEUTICALS, LLC
`Patent Owners
`
`
`
`CASE UNASSIGNED
`Patent 8,445,647
`
`
`
`DECLARATION OF S. RUSS LEHRMAN IN SUPPORT OF SANOFI-
`AVENTIS U.S. LLC AND SANOFI AVENTIS DEUTSCHLAND GMBH’S
`PETIION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,445,647
`
`SANOFI-AVENTIS Exhibit 1002 - Page 1
`IPR for Patent No. 8,445,647
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`TABLE OF CONTENTS
`
`Introduction ........................................................................................................ 1
`I.
`II. Qualifications ...................................................................................................... 2
`III. Materials Reviewed ............................................................................................ 4
`IV. The Prickett ‘647 Patent ..................................................................................... 4
`A. Background of the Technology .................................................................... 5
`B. Disclosure of the Prickett ‘647 Patent .......................................................... 7
`C. Disclosure of the Prickett ‘018 Provisional ............................................... 10
`D. The Gombotz & Pettit Article .................................................................... 14
`V. Claim Construction ........................................................................................... 21
`A. A Person of Ordinary Skill in the Art (POSITA) ....................................... 21
`B. Broadest Reasonable Interpretation ........................................................... 22
`C. Claim Terms of the Prickett ‘647 Patent .................................................... 23
`1. “Exendin-4” .......................................................................................... 23
`2. “Agonist Analogs of Exendin-4” .......................................................... 26
`3. “Polyamino Acid,” “Poly(L-Lysine),” “Poly-glutamic Acid,” and “Poly-
`aspartic Acid” ........................................................................................ 29
`4. “Linked . . . Through the C-Terminal Amino Acid” ............................ 32
`VI. Prior-Art References Disclosed All of the Elements of the Claims of the
`Prickett ‘647 Patent .......................................................................................... 34
`A. The Larsen ‘118 PCT Disclosed Each and Every Limitation of Claims 1-4
`of the Prickett ‘647 Patent .......................................................................... 36
`B. The Larsen ‘107 Patent Disclosed Each and Every Limitation of Claims 1-
`4 of the Prickett ‘647 Patent ....................................................................... 40
`C. The Larsen ‘486 and RE ‘313 Patents Disclosed Each and Every
`Limitation of Claims 1, 2, 5, and 6 of the Prickett ‘647 Patent ................. 46
`D. A Person of Ordinary Skill in the Art Would Have Been Motivated to
`Make the Invention of Claims 1-4 of the Prickett ‘647 Patent by the Larsen
`‘118 PCT .................................................................................................... 56
`E. A Person of Ordinary Skill in the Art Would Have Been Motivated to
`Make the Invention of Claims 1-4 of the Prickett ‘647 Patent by the Larsen
`‘107 Patent ................................................................................................. 61
`
`i
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`SANOFI-AVENTIS Exhibit 1002 - Page 2
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`I, S. Russ Lehrman, declare the following:
`
`I.
`1.
`
`INTRODUCTION
`
`In this proceeding before the U.S. Patent and Trademark Office (“USPTO”),
`
`I have been retained on behalf of Sanofi as an independent expert consultant.
`
`Although I am receiving compensation at my standard consulting rate of $ 300.00
`
`per hour that I spend on this proceeding, I have no other interest in its result. I also
`
`expect to be reimbursed for reasonable expenses incurred in relation to my
`
`consulting. My compensation is independent of the opinions rendered or the
`
`outcome of this proceeding.
`
`2.
`
`I understand that this proceeding involves U.S. Patent No. 8,445,647 (Ex.
`
`1001; “the Prickett ‘647 patent”) issued on May 21, 2013, and that the Prickett
`
`‘647 patent issued from U.S. Application Serial No. 13/296,120 (Ex. 1005; “the
`
`Prickett ‘120 application”) filed on November 14, 2011. I understand that the
`
`Prickett ‘120 application was a continuation of U.S. Application Serial No.
`
`11/174,089, filed June 30, 2005, which was itself a continuation of U.S.
`
`Application Serial No. 09/561,226 (Ex. 1015; “the Prickett ‘226 application”) filed
`
`April 28, 2000. Ex. 1001, col. 1, lines 6-9. I understand that the Prickett ‘226
`
`application “claims priority to, and the benefit of,” U.S. Provisional Application
`
`Serial No. 60/132,018 (Ex. 1003; “the Prickett ‘018 provisional”) filed April 30,
`
`1999. Ex. 1001, col. 1, lines 9-12.
`
`1
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`3.
`
`I have been asked by counsel for Sanofi (“counsel”) to explain the technical
`
`subject matter of the Prickett ‘647 patent and its background. I have also been
`
`asked to explain whether prior art discloses the compositions claimed in the
`
`Prickett ‘647 patent. My opinions are set forth below.
`
`II. QUALIFICATIONS
`4.
`
`Since 2006, I have been the principal of BioSuperior Technology
`
`(previously named Lehrman Biopharma), a consulting company that supports late
`
`stage research of biotechnology and pharmaceutical companies, improves drug
`
`candidate properties prior to clinical development, and supports chemistry,
`
`manufacturing and controls (“CMC”) activities at all stages of the drug
`
`development process.
`
`5.
`
`From 1985 to 1994, I was Senior Scientist at The Upjohn Company
`
`(Kalamazoo, MI). From 1994 to 1998, I was Director of Analytical Chemistry at
`
`NeXstar, Inc. (Boulder, CO). From 1998 to 2002, I was a Senior Scientist of
`
`Formulation R&D at Inhale Therapeutic Systems (later Nektar Therapeutics) in
`
`San Carlos, CA. From 2002 to 2005, I was Associate Director of Formulation
`
`Development at Elan Corporation (South San Francisco, CA). I discontinued
`
`consulting in 2011 in order to co-found Bio-NEMS Corporation (also known as
`
`SnapDNA), a company that is developing technology for rapid detection of DNA.
`
`2
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`I stopped contributing to internal operations of that company in October, 2014. At
`
`this time, I am an advisor to Bio-NEMS and have resumed my consulting practice.
`
`6.
`
`In addition to my industrial responsibilities, I held the position of Adjunct
`
`Associate Professor of Pharmaceutical Chemistry at the University of Kansas in
`
`Lawrence, Kansas from 1992 to 2013 and was a sabbatical replacement Professor
`
`at the University of San Francisco in the Department of Chemistry in 2008.
`
`7.
`
`In 1974, I received a B. Sc. in Chemistry (with distinction) from McGill
`
`University. I received a Ph.D. in Medicinal Chemistry from the University of
`
`Wisconsin, Madison in 1981. Subsequent to my doctoral work, I performed
`
`postdoctoral studies at the National Cancer Institute (Bethesda, MD) and
`
`Hoffmann-La Roche (Nutley, NJ).
`
`8.
`
`I review manuscripts for the following peer reviewed journals:
`
`Pharmaceutical Research; Journal of Pharmaceutical Science; International
`
`Journal of Pharmaceutics; Analytical Biochemistry; Biochemistry; Biochimica et
`
`Biophysica Acta; Journal of Chromatography; International Journal of Peptide
`
`and Protein Research; and Journal of Peptide Research.
`
`9.
`
`I have helped organize scientific meetings and symposia including the
`
`University of Wisconsin Land of Lakes Conferences Pharmaceutical Sciences
`
`(2003 and 2004) and the Well Characterized Biotechnology Pharmaceutical
`
`Symposium Workshops.
`
`3
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`10.
`
`I have chaired the IIR Symposium on Peptide and Protein Formulation
`
`Strategies, held in San Francisco, CA, 2002, and Well Characterized
`
`Biotechnology Pharmaceutical Symposium Workshops in 1999.
`
`11. My curriculum vitae, attached as Exhibit 1, summarizes my education and
`
`professional experience. Included in my curriculum vitae is a list of all
`
`publications that I have authored.
`
`12.
`
`In the last four years, I have provided expert testimony in a case involving
`
`the drug desloratadine, Court File No. T-1375-08; Schering Plough v. Apotex. In
`
`that case, I worked with Goodmans LLP which represented Apotex.
`
`13.
`
`I am not an attorney or patent agent and can offer no legal opinions. My
`
`opinions here are based on my professional experience, expertise, and the materials
`
`I have reviewed.
`
`III. MATERIALS REVIEWED
`14.
`
`In forming my opinions, I have reviewed the Prickett ‘647 patent, its
`
`prosecution history, and other prior-art references cited in this declaration. In
`
`particular, I have reviewed the exhibits to Sanofi’s petition listed in Exhibit 2
`
`attached hereto.
`
`IV. THE PRICKETT ‘647 PATENT
`
`4
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`A. Background of the Technology
`
`15. Treatment of individuals with Type II diabetes, particularly through the use
`
`of medications, generally involves lowering their blood glucose levels. Ex. 1016.
`
`One natural hormone that plays a key role in the lowering of blood glucose levels
`
`in humans is glucagon-like peptide 1, or GLP-1. Ex. 1018, p. 19650. GLP-1 is
`
`viewed as an important hormonal mediator in glucose homeostasis, and is secreted
`
`from intestinal L cells when nutrients are detected in the small intestine. Id. Among
`
`its other effects, GLP-1 stimulates insulin secretion and inhibits glucagon
`
`secretion, thereby in both cases lowering blood glucose, and it also helps cause a
`
`satiating effect thus preventing further ingestion of food. Exs. 1020, p. 133; 1022,
`
`p. 1316. However, GLP-1 has a very short half-life in the blood, likely lasting less
`
`than ten minutes. Ex. 1029, p. 1129, col. 1. Due to its short duration of biological
`
`activity in the body, GLP-1’s usefulness as a therapeutic agent has been considered
`
`limited, and thus alternative strategies for targeting the GLP-1 system have been
`
`sought. Ex. 1021, p.764.
`
`16. A class of peptides similar in structure to GLP-1 was found in the venom of
`
`the Gila monster and the Mexican Beaded Lizard. Ex. 1019, p. G470. It was further
`
`found that those reptile peptides, now known as exendins, were pancreatic
`
`secratagogues, meaning that they caused an increase in the secretion of certain
`
`pancreatic enzymes. Id. Exendin-3 was found in Heloderma horridum venom
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`5
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`(Mexican Beaded Lizard), whereas exendin-4 in Heloderma suspectum (Gila
`
`monster). Ex. 1024, p. 20259. Researchers reasoned that their function as
`
`pancreatic secratagogues was due to their sequence similarity to that of the GLP
`
`family. Ex. 1018, p. 19650. In fact, the naturally-occurring exendins share more
`
`than 50% sequence homology with GLP-1, as shown below in Figure 1. Id.
`
`FIGURE 1
`
`
`
`As shown above, the only structural difference between the two exendins is that
`
`exendin-3 has Ser2-Asp3 residues, whereas exendin-4 has Gly2-Glu3 residues. Ex.
`
`1025, p. 7403, col. 2, Fig. 2.
`
`17.
`
`In particular, the Heloderma genus of peptides isolated from Gila monster’s
`
`and Mexican Beaded Lizard’s venoms was studied for insulin-stimulatory action.
`
`Ex. 1018, p. 19650. Bioactive peptides exendin-3 and exendin-4 from the reptile
`
`venom indeed were found to enhance insulin secretion. Id. The minor difference in
`
`primary structure referenced above, however, results in a difference in bioactivity:
`
`Dr. John Eng found that exendin-4 produced a greater insulin response than
`
`exendin-3. Ex. 1025, p. 7402. Since he also demonstrated that the biological
`
`action of exendin-4 in the pancreas is mediated by GLP-1 receptors, exendin-4 is
`
`considered a GLP-1 receptor agonist. Id.; Ex. 1018, p. 19650.
`
`6
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`18. As a result of his discovery that the exendins had a significantly longer life-
`
`span in the body than GLP-1 (Ex. 1021), Dr. Eng proposed the use of exendins –
`
`especially exendin-4 – as a method of treatment of diabetes and the prevention of
`
`hyperglycemia by stimulating insulin release, as he claimed in U.S. Patent No.
`
`5,424,286. (Ex. 1006; “the Eng ‘286 patent”).
`
`19. A synthetic version of exendin-4, known as exenatide and marketed as
`
`Byetta®, was approved by the U.S. Food and Drug Administration in April 2005.
`
`Ex. 1026. Byetta® is an injectable prescription medicine that may improve blood
`
`sugar in patients that suffer from Type II diabetes and must be taken twice daily.
`
`Ex. 1027. However, the Byetta® package insert indicates that the drug has serious
`
`side effects, including pancreatitis or inflammation of the pancreas. Id.
`
`B. Disclosure of the Prickett ‘647 Patent
`20. The abstract of the Prickett ‘647 patent states:
`
`Novel modified exendins and exendin agonists having an exendin or
`exendin agonist linked to one or more polyethylene glycol polymers,
`for example, and related formulations and dosages and methods of
`administration thereof are provided. These modified exendins and
`exendin agonists, compositions and methods are useful in treating
`diabetes and conditions that would be benefited by lowering plasma
`glucose or delaying and/or slowing gastric emptying or inhibiting
`food intake.
`Ex. 1001 (emphasis added).
`
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`21.
`
`In addition, the Prickett ‘647 patent states:
`
`The polyethylene glycol polymers (or other molecular weight
`increasing agents) are preferably linked to an amino, carboxyl, or thio
`group, and may be linked by N or C termini of [sic] side chains of
`lysine, aspartic acid, glutamic acid, or cysteine, or alternatively, the
`polyethylene glycol polymers or other molecular weight increasing
`agents may be linked with diamine and dicarboxylic groups. The
`exendin or exendin agonist is preferably linked to the polyethylene
`glycol polymers or other molecular weight increasing agents through
`an epsilon amino group on a lysine amino acid of the exendin or
`exendin agonist.
`Ex. 1001, col. 5, ll. 29-39.
`
`22.
`
`In addition, Formulas I to VIII, Examples 1 to 10, and other embodiments
`
`that are “within the following claims” of the Prickett ‘647 patent describe only
`
`exendins or exendin analogs not containing molecular weight enhancing agents or
`
`poly(ethylene glycol) (“PEG”) polymers linked to an exendin or exendin agonist.
`
`See Ex. 1001, col. 12, l. 18-col. 25, l. 37; col.30, l. 52-col. 38, l. 22; col. 40, l. 6.
`
`23. The claims of the Prickett ‘647 patent do not relate to such a composition.
`
`Rather, the claims relate to an exendin or exendin agonist linked to a polyamino
`
`acid. For example, claim 1 of the Prickett ‘647 patent, the only independent claim,
`
`reads:
`
`A compound comprising exendin-4, or agonist analog of exendin-4,
`linked to a polyamino acid through the C-terminal amino acid of the
`
`8
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`exendin-4 or agonist analog of exendin-4 and wherein the polyamino
`acid is selected from the group consisting of poly(L-lysine), poly-
`glutamic acid, and poly-aspartic acid.
`Ex. 1001 (emphasis added).
`
`24. There is only one mention of poly(amino acids) in the specification of the
`
`Prickett ‘647 patent, specifically in the “Summary of the Invention” section:
`
`[T]he present invention provides a modified exendin or exendin
`agonist having an exendin or exendin agonist linked to one or more
`polyethylene glycol polymers or other molecular weight increasing
`compounds. A “molecular weight increasing compound” is one that
`can be conjugated to an exendin or exendin agonist and thereby
`increase the molecular weight of the resulting conjugate.
`Representative examples of molecular weight increasing compounds,
`in addition to PEG, are polyamino acids (e.g., poly-lysine, poly-
`glutamic acid, and poly-aspartic acid; see Gombotz, et al. (1995),
`Bioconjugate Chem., vol. 6: 332-351; Hudecz, et al. (1992),
`Bioconjugate Chem., vol. 3, 49-57; Tsukada, et al. (1984), J. Natl.
`Cancer Inst., vol 73: 721-729; Pratesi, et al. (1985), Br. J. Cancer, vol.
`52: 841-848), particularly those of the L conformation,
`pharmacologically inactive proteins (e.g., albumin; see Gombotz, et
`al. (1995) and the references cited therein), gelatin (see Gombotz, et
`al. (1995) and the references cited therein), succinyl-gelatin (see
`Gombotz, et al. (1995) and the references cited therein),
`(hydroxypropyl)-methacrylamide (see Gombotz, et al. (1995) and the
`references cited therein), a fatty acid, a olysaccaride, [sic] a lipid
`amino acid, and dextran.
`
`9
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`Ex. 1001, col. 4, ll. 36-57.
`
`25. The only other reference to materials other than PEG linked to exendins or
`
`exendin agonists is found in the “Detailed Description of the Invention” and is not
`
`related to polyamino acids:
`
`The present invention also provides for conjugation of an exendin or
`exendin agonist to one or more polymers other than polyethylene
`glycol which can regulate kidney clearance in a manner similar to
`polyethylene glycol. Examples of such polymers include albumin and
`gelatin. See, Gombotz and Pettit, Bioconjugate Chem., 6:332-351,
`1995, which is incorporated herein by reference in its entirety.
`Ex. 1001, col. 27, ll. 35-41.
`
`26. The remainder of the specification of the Prickett ‘647 patent, to the extent
`
`that it relates to molecular weight increasing compounds, relates only to PEG,
`
`albumin, or gelatin linked to an exendin or exendin agonist.
`
`C. Disclosure of the Prickett ‘018 Provisional
`27. Like the Prickett ‘647 patent, the Prickett ‘018 provisional generally focuses
`
`on PEG linked to an exendin or exendin agonist. It contains no mention of
`
`polyamino acids in the specification. The “Summary of the Invention” section of
`
`the application begins as follows:
`
`The present invention relates to novel modified exendins and exendin
`agonists having an exendin or exendin agonist linked to one or more
`polyethylene glycol polymers (or other molecular weight increasing
`agents), and related products and methods that are useful, for
`10
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`example, in the treatment of diabetes, including Type I and II
`diabetes, in the treatment of disorders which would be benefited by
`agents which modulate plasma glucose levels, and in the treatment of
`disorders which would be benefited by the administration of agents
`useful in modulating the rate of gastric emptying or food intake,
`including obesity, eating disorders, and insulin-resistance syndrome.
`Ex. 1003, p. 10, ll. 1-13.
`
`28.
`
`In the paragraph comparable to the one mentioning poly(amino acids) in the
`
`specification of the Prickett ‘647 patent, the Prickett ‘018 provisional states only:
`
`[T]he present invention provides a modified exendin or exendin
`agonist having an exendin or exendin agonist linked to one or more
`polyethylene glycol polymers (or other molecular weight increasing
`agents).
`Ex. 1003, p. 11, ll. 12-15.
`
`29. The “Detailed Description of the Invention” section of the Prickett ‘018
`
`provisional also does not mention polyamino acids, but includes the same language
`
`regarding materials other than PEG later found in the Prickett ‘647 patent:
`
`The present invention also provides for conjugation of an exendin or
`exendin agonist to one or more polymers other than polyethylene
`glycol which can regulate kidney clearance in a manner similar to
`polyethylene glycol. Examples of such polymers include albumin and
`gelatin. See, Gombotz and Pettit, Bioconjugate Chem., 6:332-351,
`1995, which is incorporated herein by reference in its entirety.
`Ex. 1003, p. 59, ll. 1-8.
`
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`30. Thus, the Prickett ‘018 provisional does not expressly mention poly(amino
`
`acids) at all.
`
`31. A person of ordinary skill in the art (“POSITA”), as defined below, would
`
`understand that conjugation, as described by Prickett, is a synthetic strategy in
`
`which two independent compounds, each containing at least one reactive
`
`functional group (for example, a carboxylic acid or amine), are mixed using
`
`reaction conditions that lead to formation of a covalent cross-link. See, e.g., Ex.
`
`1001, col. 27, ll. 9-29. Alternatively, the two compounds can be cross-linked using
`
`a third compound that forms one or more bridges between the compounds.
`
`32. As Prickett writes:
`
`Since exendin-4 and other exendins and exendin agonists can be
`prepared by solid phase peptide chemistry techniques, a variety of
`moieties containing diamino and dicarboxylic groups with orthogonal
`protecting groups can be introduced for conjugation to PEG.
`
`
`Ex. 1001, col. 27, ll. 29-34; see also Ex. 1003, p. 59, ll. 27-31. A POSITA would
`
`understand that moieties containing diamino (e.g., lysine) and dicarboxylic groups
`
`(e.g., glutamic and aspartic acids) are orthogonally protected to enable assembly of
`
`the peptide chain. In this instance, PEG and other molecular weight enhancing
`
`compounds are normally added after assembly of a peptide is complete and
`
`protecting groups have been removed. However, to the extent that a POSITA
`
`understood that passage of the specification of the Prickett ‘647 patent, he or she
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`would likely not understand that a peptide, assembled by solid phase chemistry
`
`techniques, could be conjugated to PEG using bridging compounds that contain
`
`diamino and dicarboxylic acid groups with orthogonal protecting groups.
`
`33. Consistent with the addition of molecular weight increasing agents after
`
`assembly of the peptide, examples in the Prickett ‘647 patent and ‘018 provisional
`
`describe synthesis of exendin and exendin agonists by solid phase chemistry
`
`techniques prior to any synthetic steps that add PEGs or other molecular weight
`
`increasing agents to these compounds. See, e.g., Ex. 1001, col. 25, l. 52-col. 26, l.
`
`40; Ex. 1003, p. 53, l. 14-p. 56, l. 29.
`
`34. Although the Prickett ‘647 patent seems to suggest that the invention could
`
`be a different method of making modified exendins using solid-phase synthesis to
`
`conjugate the peptide to PEG (or other molecular weight increasing agents), the
`
`rest of the specification provides no support for those statements. That is, the
`
`specifications of the Prickett ‘647 patent and ‘018 provisional state:
`
`The present invention also features a method of making a modified
`exendin or exendin agonist. The method involves linking one or more
`polyethylene glycol polymers or other molecular weight increasing
`agents to an exendin or exendin agonist. In preferred embodiments,
`linking is performed by solid-phase synthesis.”
`Ex. 1001, col. 5, ll. 40-45; Ex. 1003, p. 13, ll. 6-11. However, the data provided
`
`supports only the use of solid phase synthesis in the construction of exendin or
`
`13
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`exendin agonists, prior to the addition of PEG or other molecular weight enhancing
`
`agents. No information on how the latter compounds are attached to exendin or
`
`exendin agonists utilizing solid phase methods is included in the patents or
`
`provisional. Even through citation, the Prickett ‘647 patent alludes only to
`
`methods for PEG conjugation to peptides in aqueous media following the
`
`completion of solid phase synthesis, not as part of solid phase synthesis.
`
`35. A POSITA would understand that conjugation using the approach described
`
`above is fundamentally different from the method described in the Larsen patents
`
`discussed herein. The Larsen patents describe the synthetic addition of well-
`
`defined poly(amino acid) regions at the C-terminus of peptides as an integral part
`
`of the solid phase peptide chemistry process.
`
`The Gombotz & Pettit Article
`D.
`36. Both the Prickett ‘647 patent and Prickett ‘018 provisional state that they
`
`incorporate by reference an article by Wayne R. Gombotz and Dean K. Pettit,
`
`“Biodegradable Polymers for Protein and Peptide Drug Delivery,” Bioconjugate
`
`Chem., 6:332-351 (1995) (Ex. 1004; the “Gombotz & Pettit article”). The
`
`incorporation by reference is in support of the statement that examples of
`
`“polymers other than polyethylene glycol which can regulate kidney clearance in a
`
`manner similar to polyethylene glycol . . . include albumin and gelatin.” Ex. 1001,
`
`col. 27, ll. 35-41; Ex. 1003, p. 59, 11. 1-8.
`
`14
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`37. The Gombotz & Pettit article was a review of options for biodegradable
`
`polymers for drug delivery. There was notably little discussion of PEG itself,
`
`beyond indicating that it has a long history as an excipient in the pharmaceutical
`
`industry and providing specific examples of proteins that have used PEG for
`
`delivery. See Ex. 1004, pp. 333-334. PEG was also mentioned as a protein
`
`modifier to enhance delivery of two proteins in PLGA delivery systems. Id., p.
`
`335. The article reported examples from the literature of polymers for controlled
`
`release, including four types of bulk-erosion polymers, two types of surface-
`
`erosion polymers, and eleven types of hydrogel systems (as well as composite
`
`systems). Id., pp. 337-344. Gelatin and albumin appear together in the hydrogel
`
`system section. Id., p. 343.
`
`38. Polyamino acids were mentioned in the Gombotz & Pettit article in a
`
`different section of the article on protein-polymer conjugates. Id., pp. 344-346.
`
`Unlike the other described systems, the article noted the problems and
`
`unpredictability associated with those types of protein-polymer conjugates:
`
`Problems associated with conjugating polymers and proteins often
`involve inactivation or alteration of protein activity. While
`convenient conjugation chemistries take advantage of the ε-amino
`group of lysine or carboxylic acid side chains, proteins which are
`conjugated with polymers at these positions often suffer from
`inactivation or alteration of bioactivity. The extent of inactivation or
`alteration is protein specific, depending on the position of the
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`conjugation sites relative to the active region of the protein
`molecule.
`Id., pp. 344-345 (emphasis added).
`
`39. A POSITA reviewing the Gombotz & Pettit article would have understood
`
`that a functional peptide-poly(amino acid) conjugate of the type discussed in that
`
`section would have been distinct from conjugates formed with PEG or with
`
`pharmaceutically inactive proteins such as albumin and gelatin. For that matter, a
`
`POSITA reviewing the Gombotz & Pettit article would have understood that a
`
`functional peptide-poly(amino acid) conjugate of the type discussed in that section
`
`would have been distinct from peptides that include poly(amino acids) attached in
`
`the manner described by the Larsen patents. As the Gombotz & Pettit article
`
`makes clear, the issue is specific to the bioactive protein (or peptide), as well as
`
`“molecular weight increasing agent” specific.
`
`40. The Gombotz & Pettit article further noted that:
`
`Unlike poly(ethylene glycol), poly(amino acids) are negatively
`charged at physiological pH, and this charge influences their
`biological behavior. For example, circulation half-lives of poly(amino
`acids) have been demonstrated to depend on electrical charging as
`well as molecular weight.
`Id., p. 345 (emphasis added).
`
`41. Since albumin and gelatin are proteins, they have negatively and positively
`
`charged functional groups. The charge density of these proteins is significantly
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`lower than poly(amino acids). Therefore, any charge-related biological behaviors
`
`will differ between albumin and gelatin, on one hand, and poly(amino acids), on
`
`the other.
`
`42. The Gombotz & Pettit article also expressly warned that peptide-polymer
`
`conjugates – which would include peptide-poly(amino acid) conjugates – would
`
`“often” be inactive or have altered activity, and the inactivity would be peptide-
`
`specific. Id., p. 344-345. A POSITA would have received no specific guidance
`
`from the Gombotz & Pettit article on how to maintain biological activity. Thus, it
`
`is my opinion that the Gombotz & Pettit article would not have enabled a POSITA
`
`to make a biologically active peptide conjugate with a poly(amino acid).
`
`43. The Gombotz & Pettit article also specifically distinguished poly(amino
`
`acids) from PEG in terms of how they functions in biological systems. Ex. 1004,
`
`p. 345. With regard to peptide-PEG conjugates, it stated:
`
`Other potential advantages of forming protein-polymer conjugates
`include the reduction of antigenicity of the protein (179, 180),
`improvement of protein solubility (181), and a reduction in the
`susceptibility of a protein to proteolysis (182) (also see refs 183-185
`for reviews).
`Id., p. 344. Among other things, a POSITA would have understood from this
`
`quote that conjugation of a PEG to a peptide, in contrast to conjugation of a
`
`poly(amino acid), would make the peptide less antigenic.
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`17
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`44. With regard to peptide-poly(amino acid) conjugates, the Gombotz & Pettit
`
`article stated:
`
`One family of polymers which has been widely reported as
`biodegradable carriers for synthetic pharmaceuticals are polyamino
`acids: poly(L-lysine) (191), poly(L-glutamic acid) (192), and poly(L-
`aspartic acid) (193). Numerous reports of conjugating peptides to
`poly(amino acids) suggest that these carriers could also be useful in
`protein drug delivery applications; however, few reports exist in the
`literature. In order to be biodegradable, the monomers used in the
`preparation of these polymers must be of the L configuration, the D
`configuration being non-biodegradable. Poly(amino acids) offer
`chemical versatility with regard to protein or peptide conjugation
`(194, 195) and control of the backbone degradation rate (196, 197).
`Unlike poly(ethylene glycol), poly(amino acids) are negatively
`charged at physiological pH, and this charge influences their
`biological behavior. 1 For example, circulation half-lives of
`poly(amino acids) have been demonstrated to depend on electrical
`charging as well as molecular weight (198). Another biological
`feature of poly(amino acids) which is most likely related to electrical
`
`
`1 Although it does not affect the ultimate conclusion reached by Gombotz & Pettit,
`
`not all poly(amino acids) are negatively charged at physiological pH. While some,
`
`such as poly(aspartic acid) and poly(glutamic acid) are indeed negatively charged,
`
`some others, such as poly(lysine), are positively charged.
`
`
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`

`
`charging is their propensity to serve as adjuvants for conjugated
`peptides and elicit an immune response (199, 200).2 This would
`clearly be an undesirable feature in many protein drug delivery
`applications.
`Id., p. 345 (emphasis added).
`
`45.
`
` In this paragraph, the Gombotz & Pettit article specifically contrasted
`
`peptide-poly(amino acid) conjugates and peptide-PEG conjugates, going so far as
`
`to suggest that the former – unlike the latter – would have at least one “undesirable
`
`feature in many protein [or peptide] drug delivery systems,” specifically the
`
`antigenicity of peptide-poly(amino acid) conjugates. Id. A POSITA would have
`
`understood this paragraph as indicating that poly(amino acids) would have
`
`attributes that are fundamentally different from PEG when linked to peptides.
`
`46.
`
` The Gombotz & Pettit article also indicated:
`
`The kidney glomerular membrane serves to clear small circulating
`molecules (less than 70 kDa) by filtration. Conjugation of low
`molecular weight proteins with water s