DECLARATION OF MILTON BROWN, M.D., PH.D.
`Inter Partes Review of U.S. Patent No. 5,856,336
`
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`PETITION FOR INTER PARTES REVIEW
`
`In re Inter Partes Review of
`
`U.S. Patent No. 5,856,336
`
`Yoshihiro FUJIKAWA, et al.
`
`Issued: Jan. 5, 1999
`
`Application No.: 07/883,398
`
`Filed: May 15, 1992
`
`For: QUINOLINE TYPE MEVALONOLACTONES
`
`DECLARATION OF DR. MILTON BROWN, M.D., PH.D.
`
`TABLE OF CONTENTS
`
`
`
`I.
`
`STATE OF THE PRIOR ART ........................................................................................................................... 10
`
`II.
`
`THE DISCLOSURE OF KESSELER RENDERS CLAIMS 1 AND 2 OF THE ‘336 PATENT OBVIOUS ......................... 16
`
`1.
`A person having ordinary skill in the art would have selected Kesseler’s compound IIac as a lead
`compound .......................................................................................................................................................... 18
`2.
`A person having ordinary skill in the art would have found it obvious to have made the fused-ring
`analogue of compound IIac ................................................................................................................................ 20
`3.
`A person having ordinary skill in the art would have found it obvious to have selected the ½ calcium salt
`25
`
`The methods of claim 2 would have been obvious ................................................................................... 27
`4.
`THE RESULTS SHOWN IN THE DECLARATIONS WERE NOT UNEXPECTED ........................................................................... 28
`
`B.
`
`THE DECLARATIONS DO NOT COMPARE THE COMPOUND OF FORMULA A OF CLAIMS 1 AND 2 OF THE ‘336
`III.
`PATENT WITH THE CLOSEST COMPOUNDS OF THE PRIOR ART............................................................................. 31
`
`IV.
`
`
`JP ‘224 AND JP ‘585 DO NOT CONTAIN A WRITTEN DESCRIPTION OF CLAIMS 1 AND 2 OF THE ‘336 PATENT
`34
`
`V.
`
`CLAIMS 5 AND 10 OF U.S. APPLICATION NO. 07/233,752............................................................................ 39
`
`VI. CLAIM 1 OF THE ‘336 PATENT IS OBVIOUS OVER THE CLAIMS IN THE ‘752 APPLICATION ........................... 47
`
`EVIDENCE SUBMITTED DURING PROSECUTION OF THE ‘336 PATENT DOES NOT COMPARE THE
`VII.
`COMPOUND OF FORMULA A OF CLAIMS 1 AND 2 OF THE ‘336 PATENT WITH THE COMPOUNDS CLAIMED IN THE
`‘752 APPLICATION ............................................................................................................................................... 49
`
`
`
`1.
`
`I, Milton Brown, hereby declare and state:
`
`1
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`DECLARATION OF MILTON BROWN, M.D., PH.D.
`Inter Partes Review of U.S. Patent No. 5,856,336
`
`2.
`
`THAT I am a citizen of the United States;
`
`3.
`
`THAT I received the degree of Ph.D. in synthetic chemistry from University
`
`of Alabama at Birmingham in 1995 and a medical degree at the University of
`
`Virginia in 1999;
`
`4.
`
`I received postdoctoral training in the Department of Chemistry at Virginia,
`
`and in 2000 became an assistant professor of chemistry in the same department. In
`
`2003, I was promoted to Associate Professor and tenured at the University of
`
`Virgina. In June of 2006, I accepted the position as Director of the Drug
`
`Discovery Program (DDP) at the Georgetown University Medical Center (GUMC,
`
`or University) which manages and supports the University drug discovery and
`
`development efforts. I was appointed as the Edwin H. Richard and Elisabeth
`
`Richard von Matsch Endowed Chair in Experimental Therapeutics and Tenured
`
`Associate Professor in the Department of Oncology and Associate Director for the
`
`experimental therapeutics program in the Lombardi Comprehensive Cancer Center
`
`(LCCC). I also hold secondary faculty appointments in the departments of
`
`Neuroscience and Biochemistry at GUMC.
`
`5.
`
`I have more than 18 years of experience in drug discovery and currently
`
`directs the DDP at GUMC. The DDP is a program established in July of 2006 to
`
`support translational research at the LCCC at GUMC. The mission of the DDP is
`
`to discover new drug treatments and diagnostic tools for cancer using integrated
`
`2
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`DECLARATION OF MILTON BROWN, M.D., PH.D.
`Inter Partes Review of U.S. Patent No. 5,856,336
`
`sciences to improve the healthcare of our patients. As leader of the DDP, I created
`
`a new paradigm to catalyze research at GUMC and the LCCC in the area of new
`
`experimental therapeutics and personalized medicine. This has led to new
`
`initiatives, multi-institutional programs, funded multi-investigator grants, and
`
`many scholarly publications and patents.
`
`6.
`
`In the DDP, I have directly managed more than 20 staff scientists, including
`
`graduate students, technicians, research instructors, post-docs and research
`
`assistant professors dedicated to the discovery of new drugs. These individuals
`
`have included synthetic chemists, medicinal chemists, pharmacologists, cancer
`
`biologists, ADME toxicity specialists, pathologists, and spectroscopists. As
`
`director of the DDP, I have managed more than 30 stand-alone drug discovery
`
`projects that include more than 40 independent scientific investigators.
`
`7.
`
`On a national level, I was appointed by the U.S. Secretary of Health
`
`Kathleen Sebelius to serve as a scientific counselor on the National Toxicology
`
`Program Board. I have served as a scientific reviewer of grants and programs for
`
`the National Institutes of Health (NIH), National Cancer Institute (NCI) Cancer
`
`Center Support Grants, Department of Defense (DOD) and the American
`
`Association for the Advancement of Science (AAAS). I was elected to the
`
`medicinal chemistry long range planning committee for the American Chemical
`
`Society (2006-2008) and helped to set the agenda policies for medicinal chemistry
`
`3
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`DECLARATION OF MILTON BROWN, M.D., PH.D.
`Inter Partes Review of U.S. Patent No. 5,856,336
`
`symposia during that time. I have reviewed research articles for nationally and
`
`internationally recognized journals. I have given more than 80 invited lectures in
`
`the USA, China, Brazil and Europe on developing global strategies for drug
`
`discovery and developing pipelines for experimental therapeutics.
`
`8.
`
`9.
`
`I am a named inventor on multiple U.S. Patents, as listed in my attached CV.
`
`I have been asked by Sawai Pharmaceutical Co., Inc. and Sawai USA
`
`(hereinafter “Sawai”) to provide my opinion regarding the patentability of claims 1
`
`and 2 of U.S. Patent No. 5,856,336 (hereinafter “the ‘336 Patent”) in view of the
`
`cited art raised in the above-captioned inter partes review (IPR). For my time
`
`spent in connection with this matter, I am being compensated at my standard rate
`
`of $500 per hour. My compensation does not depend on the outcome of the IPR.
`
`10. To prepare this Declaration, I reviewed the documents referred to in this
`
`Declaration, including:
`
`Document 1:
`
` the ‘336 Patent;
`
`Document 2:
`
`the record of the application before the U.S. Patent and
`
`Trademark Office for the ‘336 Patent (the so-called
`
`“prosecution history” of the ‘336 Patent);
`
`Document 3: U.S. Patent No. 4,761,419 (hereinafter “Picard”);
`
`Document 4: U.S. Patent No. 4,925,852 (hereinafter “Kesseler”);
`
`4
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`DECLARATION OF MILTON BROWN, M.D., PH.D.
`Inter Partes Review of U.S. Patent No. 5,856,336
`
`
`Document 5: Endo, A. et al., “Competitive Inhibition of 3-Hydroxy-3-
`
`Methylglutaryl Coenzyme A Reductase by ML-236A and ML-236B
`
`Fungal Metabolites, Having Hypocholesterolemic Activity,” FEBS
`
`Letters 1976, 72(2), 323-326 (hereinafter “Endo 1976”);
`
`Document 6: D.R. Illingsworth, “Lipid Lowering Drugs And Overview
`
`Of Indications And Optimal Therapeutic Use,” Drugs 1987, 33, 259-
`
`279 (hereinafter “Illingsworth 1987”);
`
`Document 7: D.R. Illingsworth, “An Overview Of Lipid Lowering
`
`Drugs,” Drugs 1988, 36 (Suppl. 3), 63-71 (hereinafter “Illingsworth
`
`1988”);
`
`Document 8: Alfred W. Alberts, “Mevinolin: A Highly Potent
`
`Competitive Inhibitor of Hydroxymethylglutaryl-Coenzyme a
`
`Reductase and a Cholesterol-Lowering Agent,” 77 Proc. Nat’l Acad.
`
`Sci. USA, 1980, 3957 (hereinafter “Alberts 1980”);
`
`Document 9: Brown, M., et al., Induction of 3-Hydroxy-3-
`
`methylglutaryl Coenzyme A Reductase Activity in Human Fibroblasts
`
`Incubates with Compactin "(ML-236B), a Competitive Inhibitor of the
`
`Reductase, Journal of Biological Chemistry, Vol. 253, NO. 4, 1121-
`
`1128 (Feb. 25, 1978)(hereinafter “Brown 1978”);
`
`5
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`DECLARATION OF MILTON BROWN, M.D., PH.D.
`Inter Partes Review of U.S. Patent No. 5,856,336
`
`
`Document 10: Stokker, G., et al., 3-Hydroxy-3-methylglutaryl-
`
`coenzyme A Reductase Inhibitors. 1. Structural Modifications of 5-
`
`Substituted 3,5-Dihydroxypentanoic Acids and Their Lactone
`
`Derivatives, Journal of Medicinal Chemistry, Vol. 28, 347-358 (1985)
`
`(hereinafter “Stokker”);
`
`Document 11: Brown et al, J. Chem. Soc. Perkin I, (1976); (hereinafter
`
`“Brown 1976”);
`
`Document 12: A. Endo, “Compactin (ML– 236B) And Related
`
`Compounds As Potential Cholesterol-Lowering Agents That Inhibit
`
`HMG Co-A Reductase,” J. Med. Chem. 1985, 28(4), 401-405
`
`(hereinafter “Endo 1985”);
`
`Document 13: Nakamura, C., et al., Mode of Interaction of ß-Hydroxy-
`
`ß-methylglyutaryl Coenzyme A Reductase with Strong Binding
`
`Inhibitors: Compactin and Related Compounds, Biochemistry, Vol.
`
`24, 1364-1376 (1985)(hereinafter “Nakamura”)
`
`Document 14: English translation of JP 62-207224 (hereinafter “JP
`
`‘224”);
`
`Document 15: English translation of JP 63-15585 (hereinafter “JP
`
`‘585”);
`
`6
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`DECLARATION OF MILTON BROWN, M.D., PH.D.
`Inter Partes Review of U.S. Patent No. 5,856,336
`
`
`Document 16: the record before the U.S. Patent and Trademark Office
`
`for U.S. Application No.07/631,092;
`
`Document 17: the record before the U.S. Patent and Trademark Office
`
`for U.S. Application No. 07/233,752;
`
`Document 18: the record before the U.S. Patent and Trademark Office
`
`for interference no. 102,975 (“the ‘975 interference”);
`
`Document 19: the record before the U.S. Patent and Trademark Office
`
`for interference no. 102,648 (“the ‘648 interference”);
`
`Document 20: U.S. Patent No. 4,925,825 to Tachi
`
`Document 21: U.S. Patent No. 4,375,475 to Willard (hereinafter
`
`“Willard”)
`
`Document 22: U.S. Patent No. 4,450,171 to Hoffman
`
`Document 23: U.S. Patent No. 4,686,237 to Anderson
`
`Document 24: U.S. Patent No. 4,448,784 to Glamkowski
`
`Document 25: U.S. Patent No. 4,613,610 to Wareing
`
`Document 26: U.S. Patent No. 4,735,958 to Roth
`
`Document 27: U.S. Patent No. 4,681,893 to Roth
`
`Document 28: U.S. Patent No. 4,647,576 to Hoefle
`
`Document 29: EP-A-0221025 to Wareing
`
`7
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`DECLARATION OF MILTON BROWN, M.D., PH.D.
`Inter Partes Review of U.S. Patent No. 5,856,336
`
`11.
`
`I have been asked in this Declaration to provide my opinion as to whether
`
`claims 1 and 2 of the ‘336 Patent would have been anticipated or obvious to a
`
`person having ordinary skill in the art prior to August 3, 1988 (hereinafter “August
`
`1988”) in view of the documents I discuss herein. My opinions herein are based
`
`on the contents of the documents to which I refer, and unless noted otherwise,
`
`reflect my opinion of what would have been understood in August 1988.
`
`12. As I discuss in the present Declaration, it is my opinion that the teachings of
`
`the documents I discuss herein either anticipate or render obvious claims 1 and 2 of
`
`the ‘336 Patent, as discussed herein.
`
`13.
`
`I am aware that claims 1 and 2 of the ‘336 Patent recite:
`
`1. A compound of the formula,
`
`Z= —CH(OH)—CH2—CH(OH)—CH2—COO.½Ca.
`
`
`
`8
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`DECLARATION OF MILTON BROWN, M.D., PH.D.
`Inter Partes Review of U.S. Patent No. 5,856,336
`
`
`2. A method for reducing hyperlipidemia, hyperlipoproteinemia or
`
`atherosclerosis, which comprises administering an effective amount of
`
`the compound of formula A as defined in claim 1.
`
`14. Although I am uncertain as to the meaning of the triangle in the lower right
`
`hand portion of formula A, as this is not a convention method of drawing a
`
`chemical compound, for the purposes of this Declaration, I have been asked to
`
`consider the triangle as cyclopropyl. The ‘336 Patent discloses that formula A
`
`includes all isomeric forms of the compound: “these compounds may have at least
`
`one or two asymmetric carbon atoms and may have at least two to four optical
`
`isomers. The compounds of the formula I include all of these optical isomers and
`
`all of the mixtures thereof.” At 2:66-3:2. A person having ordinary skill in the art
`
`would have understood that formula I includes four optical isomers and mixtures
`
`thereof.
`
`15.
`
`In August 1988, a person having ordinary skill in the art would have held an
`
`advanced degree, such as an M.S. or a doctorate in one of the fields of medicinal or
`
`synthetic chemistry, pharmacology, with 3 to 5 years of experience working in the
`
`field of drug discovery who was familiar with mevalonolactones, including natural,
`
`semi-synthetic and fully synthetic derivatives of compactin and mevinoline and
`
`related compounds, and their pharmaceutical uses as anti-hyperlipidemic,
`
`hypolipoproteinemic and anti-atherosclerotic agents.
`
`9
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`DECLARATION OF MILTON BROWN, M.D., PH.D.
`Inter Partes Review of U.S. Patent No. 5,856,336
`
`I.
`
`STATE OF THE PRIOR ART
`
`16. By 1988 there were a number of pharmaceutical companies researching
`
`HMG-CoA reductase inhibitors directed to use as cholesterol-lowering agents.
`
`Illingsworth 1987, pp. 275-76. In fact, Illingsworth described mevinolin and its
`
`analogues as “a major advance in the treatment of patients with primary
`
`hypercholesterolaemia.” Id. at 276.
`
`17. That advance was based on knowledge that 3-hydroxy-3-methylglutaric acid
`
`coenzyme A reductase (HMG-CoA reductase) catalyzed the conversion of HMG-
`
`CoA into mevalonic acid and that HMG-CoA reductase was a prime target for
`
`reducing, for example, hypercholesterolemia. Alberts 1980, p. 3957.
`
`18.
`
`In 1976, the inhibition of HMG-CoA reductase by the compound
`
`“compactin” was reported. Endo 1976, pg. 323. Thereafter, the inhibition of
`
`HMG-CoA reductase was a focus of ongoing drug development. See, e.g., Brown
`
`1978, p. 1121; Stokker, p. 347-358 . Compactin was later found to possess a
`
`mevalonolactone moiety. Brown 1976, p. 1165.
`
`19.
`
`Importantly, it was disclosed in the prior art that HMG Co-A reductase
`
`inhibitors compactin and mevinolin were effective in mg quantities in patients,
`
`and that both compounds, along with a related compound, MK733 were in clinical
`
`trials as of 1987. Illingsworth 1987, p. 275.
`
`10
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`DECLARATION OF MILTON BROWN, M.D., PH.D.
`Inter Partes Review of U.S. Patent No. 5,856,336
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`20. The Illingsworth review article recognized that “the open acid forms of these
`
`drugs has [sic] a similar ring structure to HMG Co-A and is presumed to be the
`
`active part of these agents in terms of their ability to inhibit HMG Co-A
`
`reductase.” Id. p. 275. This statement is consistent with earlier literature
`
`describing the open chain form of compactin as having activity comparable to the
`
`lactone in vitro and in vivo, but superior in terms of safety. See Endo 1985, p. 405.
`
`21. A person having ordinary skill in the art in 1988 would have recognized that
`
`among the various modes of treating hypercholesterolemia, HMG Co-A reductase
`
`inhibitors were among the most effective and well tolerated as first-line therapies.
`
`Persons skilled in the art would have also known that the most investigated and
`
`active of the HMG Co-A reductase inhibitors were derivatives of compactin and
`
`mevinolin -- in lactone or open chain form -- and that certain statin compounds
`
`were among the most clinically promising from the perspective of efficacy and
`
`tolerability.
`
`22. By 1985, compactin and mevinolin were used as standards for comparison
`
`of HMG-CoA reductase inhibition, and synthetic derivatives of these compounds
`
`were actively studied. Nakamura describes research directed to compactin
`
`derivatives in which the lactone ring “upper portion” of the molecule is retained,
`
`and the decalin “lower portion” of the molecule containing two fused rings is
`
`changed to a substituted single-ring phenyl group (compound 3), or to a fused two-
`
`11
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`DECLARATION OF MILTON BROWN, M.D., PH.D.
`Inter Partes Review of U.S. Patent No. 5,856,336
`
`ring naphthyl group. Id. at 1365. Although the phenyl structure of the “lower
`
`portion” of compound 3 was “entirely different from that found in compactin” its
`
`inhibiting activity as identical with that for compactin. Id. Nakamura concludes
`
`that the lower “hydrophobic region can accommodate a range of structures as
`
`evidenced by the fact that compactin and [compound] 3 bind equally well to HMG-
`
`CoA reductase, although the lower portions are quite different.” Id. at 1374. A
`
`person having ordinary skill in the art would understand from Nakamura that a
`
`range of similar single and fused ring substituents could be used in the “lower
`
`portion” of synthetic compactin analogs, as “hydrophobic anchors” in the binding
`
`of several inhibitors. Id. at 1374. Nakamura cites “a number of substituted
`
`biphenyls connected to the “top” piece of compactin” having inhibitory activities
`
`approaching compactin disclosed in U.S. Patent 4,375,475 to Willard. Willard’s
`
`preferred compound (Claim 16) has the following structure, in which the “lower
`
`portion” of the molecule is a phenyl group, substituted with a 4’-fluorophenyl
`
`group and two methyl groups:
`
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`DECLARATION OF MILTON BROWN, M.D., PH.D.
`Inter Partes Review of U.S. Patent No. 5,856,336
`
`
`
`
`23. Nakamura and Willard suggest to a person having ordinary skill in the art
`
`that both single aromatic ring synthetic analogs of compactin andfused aromatic
`
`ring analogs would both be active. Willard specifically discloses that a single
`
`phenyl ring substituted with a 4’-fluorophenyl group and a methyl group has
`
`superior inhibitory activity, as sodium salts of the corresponding hydroxyl acid
`
`forms. At 4:44-45 (6-[2-(4'-fluoro-3,3',5-trimethyl[1,1'-biphenyl]-2-yl)ethenyl]-
`
`3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one (IC50=7 x 10-9)).
`
`24. By 1988, a person having ordinary skill in the art would have looked to
`
`reduce (at least) hypercholesterolemia by developing compounds that targeted
`
`HMG-CoA reductase, and would have considered, for example, compactin or
`
`mevalonolactone derivatives, in lactone or open chain form, as promising
`
`compounds for further research.
`
`25. Among the HMG Co-A reductase inhibitors based on compactin and
`
`mevinolin that were being investigated, some appear to be based on natural
`
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`DECLARATION OF MILTON BROWN, M.D., PH.D.
`Inter Partes Review of U.S. Patent No. 5,856,336
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`products, some were synthetic, and some were semisynthetic.1 Notwithstanding,
`
`there were several important statin compounds that were being investigated by
`
`different pharmaceutical companies, all of which were lead compounds to those
`
`companies. These synthetic statins included compounds having carbocycylic core
`
`structures (phenyl, biphenyl, napthyl) as well as heterocyclic core structures
`
`(pyrrole, pyrazole, indole, quinoline, etc.) based on compactin and
`
`mevalonolactone, and many were reported in the literature.
`
`26. For example, pyrazole analogs (USP 4,613,610), pyrrole derivatives (USP
`
`4,735,958, USP 4,681,893), pyran-2-ones and derivatives (USP 4,647,576),
`
`naphthyl analogs of mevalonolactone (USP 4,686,237), furan and thiophene
`
`derivatives (EP-A-0221025), velostatin and related compounds (USP 4,448,784
`
`and 4,450,171), quinoline analogs of mevalonolactone (USP 4,761,419) and
`
`compactin (USP 4,925,852) were all reported - with differing levels of activity.
`
`Among these analogs and derivatives of mevalonolactone and compactin, the
`
`
`1 The distinction between these categories is arbitrary, inasmuch as there is no
`
`literature basis to treat the origin of the compounds as mutually exclusive. That
`
`is, a compound naturally obtained (e.g., by fermentation) could easily be the
`
`subject of a simple structural modification, or could have been the target of a
`
`synthetic scheme.
`
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`DECLARATION OF MILTON BROWN, M.D., PH.D.
`Inter Partes Review of U.S. Patent No. 5,856,336
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`quinoline-based analogs of mevalonolactone were among the most biologically
`
`active based on reported IC50 data. For example, the most active compounds in
`
`the ‘852 Patent (13w (IC50=0.9x10-9M), 13ac (IC50=1.0x10-9M)) favorably
`
`compared to the most active pyrazole analogs of mevalonolactone (see e.g., ‘610
`
`patent, Ex. 14 (IC50=0.02 µmolar), the most active pyrole derivatives (see e.g., ‘958
`
`patent (Compound 3 (IC50=13x10-9M), ‘893 patent Compound 3 (IC50=0.018
`
`µmolar)), and the naphthyl analogs of mevalonolactone (see e.g., the ‘237 patent,
`
`Example 2, (IC50=0.01 µmolar)).
`
`27. Lovastatin (mevinolin) was a HMG Co-A reductase inhibitor newly-
`
`approved by the FDA in 1987 and clinical trials of related compounds as
`
`monotherapies (simvastatin, pravastatin) demonstrated decreases in LDL
`
`cholesterol of up to 48% when dosed at 80 mg/day, a reduction that was superior to
`
`those shown by the fibrate drugs also studied. Illingsworth 1988, pp. 66-68.
`
`28. Scientists at Hoechst had patented a number of mevalonic acid derivatives as
`
`HMG Co-A reductase inhibitors disclosed as useful as cholesterol-lowering agents
`
`(‘852 patent), and the most biologically active compound reported in the ‘852
`
`patent would have been natural choices for further development by those skilled in
`
`the art. Similarly, scientists at Warner-Lambert patented a number of quinoline-
`
`based HMG Co-A reductase inhibitors, and the most active compounds reported a
`
`net patent would also have been natural choices for further development by those
`
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`DECLARATION OF MILTON BROWN, M.D., PH.D.
`Inter Partes Review of U.S. Patent No. 5,856,336
`
`skilled in the art. This is especially true since the most active compounds of these
`
`patents were more potent than many of the other compactin and mevalonolactone
`
`derivatives as discussed above.
`
`29. Accordingly, by 1988, a person having ordinary skill in the art would have
`
`looked to reduce (at least) hypercholesterolemia by developing compounds that
`
`targeted HMG-CoA reductase. They would have considered, for example,
`
`compactin or mevalonolactone derivatives, in lactone or open chain form, as
`
`promising compounds for further research.
`
`II. THE DISCLOSURE OF KESSELER RENDERS CLAIMS 1 AND 2 OF THE ‘336
`PATENT OBVIOUS
`
`30. Kesseler describes mevalonic acid derivatives useful as inhibitors of
`
`cholesterol biosynthesis, and is directed to new synthetic analogs of compactin in
`
`open chain or lactone form. Kesseler, at 1:1:50. The compounds disclosed by
`
`Kesseler “are distinguished by strong inhibition of HMG-CoA reductase, the rate-
`
`determining enzyme of cholesterol biosynthesis.” Kesseler, at 15:46-49. Table 14
`
`of Kesseler includes compound IIac. Compound IIac is structurally similar to the
`
`compound of formula A of claims 1 and 2 of the ‘336 Patent, and the table below
`
`provides a side-by-side comparison of these two compounds, with the only
`
`differences between them circled:
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`DECLARATION OF MILTON BROWN, M.D., PH.D.
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`Inter Partes Review of U.S. Patent No. 5,856,336
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`Claim 1 of the ‘336 Patent
`
`Kesseler compound Ilac
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`31. As can be seen from the above, the only two differences between the
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`compound of formula A of claims 1 and 2 of the ‘336 Patent and Kesseler’s
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`compound Ilac are (1) the fused ring of the compound of formula A of claims 1
`
`and 2 of the ‘336 Patent as opposed to the benzo-cracked ring of Kesseler’s
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`compound Ilac, and (2) the salt form of each compound. However, for the reasons
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`discussed below, a person having ordinary skill in the art would have found it
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`obvious to have altered Kesseler’s compound Ilac so as to arrive at the compound
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`of formula A of claims 1 and 2 of the ‘336 Patent.
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`DECLARATION OF MILTON BROWN, M.D., PH.D.
`Inter Partes Review of U.S. Patent No. 5,856,336
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`
`1.
`
`A person having ordinary skill in the art would have
`selected Kesseler’s compound IIac as a lead compound
`
`32. Of the hundreds of compounds possibly encompassed by Kessler’s claims,
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`Kessler specifically names about 80 compounds in the specification (Kesseler, at
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`10:4-13:62), and actually prepares approximately 20 or more compounds, both in
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`open chain (dihydroxy acid derivative) form (e.g., Table 14) and in δ-lactone form
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`(e.g., Table 1). Because Kesseler reports on the properties of these approximate 20
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`compounds in the form of IC50 data, a person having ordinary skill in the art
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`would consider the most biologically active compounds as potential candidates for
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`further research.
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`33. The data shows the most active compounds in δ-lactone form were the
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`compounds of examples 13w (IC50 = 0.9 x 10-9) and 13ac (IC50 = 1.0 x 10-9). The
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`differences in activity between these two compounds were not substantial, and
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`both would have been considered interesting possibilities for further exploration.
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`Indeed, the top performers in Table 1 would have been considered interesting
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`possibilities for further exploration. Moreover, both compounds were prepared in
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`their dihydroxy acid derivative forms as compounds IIw and IIac, respectively, and
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`a person having ordinary skill in the art would have considered the open-ring forms
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`as or more interesting than compounds 13w and 13ac, based on prior art teachings
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`DECLARATION OF MILTON BROWN, M.D., PH.D.
`Inter Partes Review of U.S. Patent No. 5,856,336
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`that the dihydroxy acid derivative of the δ-lactone ring form was reported to be
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`more active than the analogous δ-lactone form.
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`34. For example, in Alberts, it is observed that the δ-lactone compounds
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`compactin and mevinolin and their dihydroxy acid derivative analogue mevinolinic
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`acid are both inhibitors of HMG-CoA reductase, with the dihydroxy acid
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`derivative form being more active than the δ-lactone form. In Endo, four
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`compounds were tested, and although “all the four compounds were inhibitory to
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`HMG-CoA reductase,” “[t]he acid forms [i.e., open ring form] (sodium salts) of
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`both ML236A and MC236B were more effective in inhibiting the reductase than
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`their respective lactone forms.” See Endo at 323 and 325. Endo states that “[t]he
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`inhibitory potency was approximately doubled by the conversion of lactone forms
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`to their respective acid forms (sodium salts).” Id. at 324. To this end, Endo also
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`reports on the salt form of its dihydroxy acid derivative forms (see Table 1 and
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`page 324 of Endo) and reports that the salt forms are active HMG-CoA inhibitors.
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`See also Illingsworth 1987 at 275.
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`35. An immediately recognizable difference between compounds IIw and IIac
`
`can be seen at the R1 position. Many of the compounds reported on Tables 1 and
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`14 have isopropyl groups at the R1 position (including compound IIw), but only
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`compound IIac contains a cyclopropyl group at that position. A person having
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`ordinary skill in the art would have been interested in further exploring the only
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`DECLARATION OF MILTON BROWN, M.D., PH.D.
`Inter Partes Review of U.S. Patent No. 5,856,336
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`exemplified compound having a cyclopropyl group at the R1 position, and which
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`also had remarkable activity. That is because compounds having a cyclopropyl
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`group at the R1 position were less explored in the literature and may have offered
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`certain synthetic opportunities over the more well reported isopropyl compounds.
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`36. However, a person having ordinary skill in the art would not have needed
`
`the above biological data in order to have selected compounds IIw or IIac as
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`starting points, but the presence of this biological data further supports my opinion
`
`that a person having ordinary skill in the art would have selected compound IIac of
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`Kesseler when determining a starting point for making an active HMG-CoA
`
`reductase inhibitor.
`
`2.
`
`A person having ordinary skill in the art would have found
`it obvious to have made the fused-ring analogue of
`compound IIac
`
`37. Turning to the changes that a person having ordinary skill in the art would
`
`have needed to make to compound IIac of Kesseler so as to arrive at the compound
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`of formula A of claims 1 and 2 of the ‘336 Patent, as I noted above, only two
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`changes need to be made, and both would have been obvious to a person having
`
`ordinary skill in the art.
`
`38. The first change to Kesseler’s compound IIac that would have been needed
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`is the change from the biphenyl structure of compound IIac to the fused ring
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`DECLARATION OF MILTON BROWN, M.D., PH.D.
`Inter Partes Review of U.S. Patent No. 5,856,336
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`structure of the compound of formula A of claims 1 and 2 of the ‘336 Patent.
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`However, this change would have been obvious to a person having ordinary skill in
`
`the art. I have previously discussed the design process of benzofusion, which
`
`again is roughly illustrated in the figure below:
`
`
`
`39. Given a split-ring compound, such as compound A in the figure above, a
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`person having ordinary skill in the art would have naturally attempted to create a
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`compound containing fused rings in order to further develop the compound. This
`
`is because ring-fused compounds (compound B in the figure) were generally
`
`accepted being analogs of their ring-cracked counterparts (compound A in the
`
`figure), and vice-versa.
`
`40. For example, the ring-cracked compounds in Kesseler are disclosed as being
`
`analogues of the known ring-fused HMG-CoA reductase inhibitor compactin.
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`Kesseler at 1:31-34 (“The present invention relates to new synthetic analogs of
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`“compactin” in the form of the δ–lactone of the formula I or in the form of the
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`dihydroxy acid derivative II”). I understand that the structure of compactin is:
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`DECLARATION OF MILTON BROWN, M.D., PH.D.
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`Inter Partes Review of U.S. Patent No. 5,856,336
`
`41.
`
`Accordingly, Kesseler teaches the analogue nature of ring-fused and ring-
`
`cracked compounds in the HMG—CoA reductase inhibitor context. The analogous
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`nature of ring-fused and ring-cracked compounds is also evidenced by a
`
`comparison of the chemical structures of the HMG—CoA reductase inhibitors in
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`Picard and Kesseler. In particular, Picard discloses the activity of two of its
`
`compounds in Table 1. The two compounds in Picard’s Table 1 are analogues of
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`two of the compounds in Kesseler:
`
`Compounds in
`
`Kesseler Compound Ic
`
`Compound 1e
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`DECLARATION OF MILTON BROWN, M.D., PH.D.
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`Inter Partes Review of U.S. Patent No. 5,856,336
`
`Analogous
`compounds in Table
`
`1 of Picard
`
`42.
`
`The only differences between these two compounds are that the compounds
`
`of Picard are ring-fused with a chlorine substituent, and the compounds of Kesseler
`
`are ring-cracked. Table 1 of Picard shows that its compounds above are active
`
`HMG—CoA reductase inhibitors by virtue of the IC5o values reported therein. Table
`
`1 of Kesseler similarly shows that its above compounds are active HMG—CoA
`
`reductase inhibitors by virtue of the IC50 values reported therein. A person having
`
`ordinary skill in the art therefore would have seen the clear structural similarity
`
`between these compounds, would have seen that each were reported as being
`
`active HMG—CoA reductase inhibitors, and would have seen Kesseler’s teachings
`
`that its ring-cracked compounds (i.e., those of formulae I and II in Kesseler) were
`
`“analogs” of the ring—fused structure of compactin. At least based on those
`
`reasons, the person having ordinary skill in the art would have understood that the
`
`classical medicinal chemistry transformation resulting in ring—fused and ring-
`
`cracked compounds in the HMG—CoA area were recognized analogues. See also
`
`Nakamura at 1374 (discus