UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`PAR PHARMACEUTICAL, INC.,
`
`Petitioner,
`
`v.
`
`NOVARTIS AG,
`
`Patent Owner.
`
`Case IPR2016-00084
`Patent No. 5,665,772
`
`EXPERT DECLARATION OF PROFESSOR
`ALEXANDER M. KLIBANOV
`
`NOVARTIS EXHIBIT 2092
`Par v Novartis, IPR 2016-00084
`Page 1 of 104
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`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`PAR PHARMACEUTICAL, INC.,
`
`Petitioner,
`
`v.
`
`NOVARTIS AG,
`
`Patent Owner.
`
`Case IPR2016-00084
`Patent No. 5,665,772
`
`EXPERT DECLARATION OF PROFESSOR
`ALEXANDER M. KLIBANOV
`
`NOVARTIS EXHIBIT 2092
`Par v Novartis, IPR 2016-00084
`Page 1 of 104
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`
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`TABLE OF CONTENTS
`
`I.
`
`II.
`
`III.
`
`IV.
`
`V.
`
`QUALIFICATIONS........................................................................................1
`
`ASSIGNMENT................................................................................................4
`
`SUMMARY OF OPINIONS...........................................................................5
`
`LEGAL PRINCIPLES.....................................................................................7
`
`A.
`
`B.
`
`Obviousness...........................................................................................7
`
`A Person Of Ordinary Skill In The Art.................................................9
`
`GROUNDS 1 AND 2 ARE BASED ON THE ALLEGATION
`THAT ONE CLAIMED COMPOUND, EVEROLIMUS, IS
`OBVIOUS......................................................................................................10
`
`VI. ONE OF ORDINARY SKILL SEEKING TO INCREASE
`RAPAMYCIN’S WATER SOLUBILITY WOULD NOT
`HAVE BEEN MOTIVATED TO SYNTHESIZE
`EVEROLIMUS OR HAD A REASONABLE EXPECTATION
`THAT IT WOULD HAVE INCREASED WATER
`SOLUBILITY................................................................................................14
`
`A.
`
`B.
`
`Rapamycin And Everolimus Both Have An Alcohol
`Hydroxyl Functional Group At Their C40 Positions;
`However, Everolimus Has An Ether Oxygen And An
`Ethylene Group While Rapamycin Does Not .....................................14
`
`Lemke Does Not Provide A Motivation To Modify
`Rapamycin To Arrive At Everolimus, Nor A Reasonable
`Expectation That Everolimus Will Have Increased Water
`Solubility .............................................................................................16
`
`1.
`
`Par’s Reliance On Lemke Ignores The Undisputed
`Similarities And Differences Between The
`Chemical Structures Of Rapamycin And
`Everolimus ................................................................................16
`
`i
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`2.
`
`3.
`
`4.
`
`5.
`
`If A Person Of Ordinary Skill Were To Interpret
`Lemke As Par And Dr. Jorgensen Suggested, He
`Or She Would Not Have Arrived At Everolimus.....................19
`
`According To Lemke, Inserting An Ethyleneoxy
`Group Would Not Have Been Expected To
`Improve Rapamycin’s Water Solubility ...................................21
`
`Lemke Would Have Suggested Modifications
`Other Than Insertion Of An Ethyleneoxy Group .....................25
`
`Dr. Jorgensen’s New Deposition Arguments Do
`Not Reflect How One Of Ordinary Skill Would
`Have Interpreted Lemke’s Teachings And Ignore
`The Reference As A Whole ......................................................31
`
`C.
`
`D.
`
`Dr. Jorgensen’s New Deposition Argument That Primary
`Alcohols Would Have Been Reasonably Expected To
`Impart Greater Solubility Than Secondary Alcohols Is
`Unsupported ........................................................................................35
`
`Yalkowsky Does Not Provide A Motivation To Modify
`Rapamycin To Arrive At Everolimus, Nor A Reasonable
`Expectation That Everolimus Will Have Increased Water
`Solubility .............................................................................................38
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`Overview Of Par’s Arguments..................................................38
`
`Dr. Jorgensen Acknowledged That Yalkowsky Is
`Not Relevant Prior Art..............................................................40
`
`Yalkowsky Concerns Ideal Solubility, But Because
`Water Is Not An Ideal Solvent For Rapamycin,
`Yalkowsky Is Not Applicable To Rapamycin’s
`Solubility In Water....................................................................42
`
`Yalkowsky Teaches That Estimation Of Ideal
`Solubility Requires Knowledge Of Melting Point,
`Which Was Not Known For Everolimus..................................48
`
`Yalkowsky’s Discussion Of “Long Chain
`Derivatives” Is Not Applicable To The Short
`
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`Chain 2-Hydroxyethyl Ether C40 Derivative Of
`Rapamycin That Is Everolimus.................................................49
`
`Rapamycin Is Not A Rigid Molecule Under
`Yalkowsky ................................................................................59
`
`Rapamycin Is Not A Molecule Of Intermediate
`Size Under Yalkowsky .............................................................61
`
`Yalkowsky Contradicts Dr. Jorgensen’s Position
`That One Of Ordinary Skill Would Pursue The
`Smallest Possible Modifications...............................................62
`
`Dr. Jorgensen’s New Figure 2 Deposition
`Argument Does Not Change My Opinions...............................64
`
`6.
`
`7.
`
`8.
`
`9.
`
`10. According To Yalkowsky, A 2-Hydroxyethyl
`Ether Would Not Have Been Reasonably Expected
`To Improve Rapamycin’s Water Solubility..............................70
`
`Dr. Jorgensen’s Reliance On Polyethyleneoxy (PEG)
`Groups Is Neither Supported Nor Relevant To The
`Addition Of A Single Ethyleneoxy Group To Rapamycin.................71
`
`Dr. Jorgensen’s Antihistamine And β-Blocker Examples
`Do Not Support His Motivation To Modify Or
`Reasonable Expectation of Success Arguments .................................76
`
`Dr. Jorgensen Was Unable To Quantify Everolimus’s
`Expected Water Solubility As Compared To Rapamycin
`Or Explain How Or Why One Of Ordinary Skill Would
`Have Expected Everolimus To Overcome Rapamycin’s
`Alleged Poor Water Solubility ............................................................79
`
`E.
`
`F.
`
`G.
`
`H.
`
`Conclusion...........................................................................................83
`
`VII. A PERSON OF ORDINARY SKILL WOULD NOT HAVE
`CONSIDERED RAPAMYCIN’S WATER SOLUBILITY TO
`BE A PROBLEM THAT NEEDED TO BE ADDRESSED ........................84
`
`A.
`
`Dr. Jorgensen And Par Improperly Rely On Statements
`About Rapamycin’s Water Solubility In The ’772 Patent
`
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`Specification That Do Not Represent The State Of The
`Art........................................................................................................84
`
`B. Morris Did Not Suggest That Rapamycin’s Water
`Solubility Was A Problem That Needed To Be
`Addressed ............................................................................................85
`
`C.
`
`Stella Did Not Suggest That Rapamycin’s Water
`Solubility Was A Problem That Needed To Be
`Addressed ............................................................................................87
`
`VIII. IF A PERSON OF ORDINARY SKILL WANTED TO
`IMPROVE RAPAMYCIN’S WATER SOLUBILITY AND
`ALLEGED POOR BIOAVAILABILITY, HE OR SHE
`WOULD HAVE PURSUED FORMULATION, PRODRUG,
`OR WATER-SOLUBLE SALT APPROACHES—NOT
`EVEROLIMUS..............................................................................................88
`
`A.
`
`B.
`
`C.
`
`A Person Of Ordinary Skill Would Have Addressed
`Rapamycin’s Alleged Poor Water Solubility And
`Bioavailability Issues Using Formulation Approaches.......................88
`
`A Person Of Ordinary Skill Would Have Addressed
`Rapamycin’s Alleged Poor Water Solubility And
`Bioavailability Issues Using Prodrugs ................................................91
`
`A Person Of Ordinary Skill Would Have Addressed
`Rapamycin’s Alleged Poor Water Solubility And
`Bioavailability Issues Using Water-Soluble Salts ..............................97
`
`iv
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`I, Alexander M. Klibanov, Ph.D., declare as follows:
`
`1.
`
`I submit this expert declaration in response to certain arguments made
`
`in Par Pharmaceutical, Inc.’s (“Par’s”) Petition For Inter Partes Review Of U.S.
`
`Patent No. 5,665,772 (IPR2016-00084, Paper 2, “Pet.”) requesting IPR of claims
`
`1-3 and 8-10, and the Declaration of William L. Jorgensen, Ph.D., in Support of
`
`Petition for Inter Partes Review of U.S. Patent No. 5,665,772 (Ex. 1003,
`
`“Jorgensen Decl.”).
`
`I.
`
`QUALIFICATIONS
`
`2.
`
`I am a Novartis Endowed Chair Professor of Chemistry and
`
`Bioengineering at the Massachusetts Institute of Technology (“M.I.T.”), where I
`
`have been teaching and conducting research for over 37 years.1 In 2012-2013, I
`
`held the Roger and Georges Firmenich Endowed Chair Professorship in Chemistry
`
`and Bioengineering, and in 2007-2012, the same chaired professorship as I
`
`currently hold. Prior to that, I was a Professor of Chemistry and a Professor of
`
`Bioengineering at M.I.T., positions I held from 1988 and 2000, respectively. From
`
`1979 to 1988, I was an Assistant Professor, then Associate Professor, and
`
`1 Novartis has no say in who receives this chair or my compensation at M.I.T., and
`
`my title at M.I.T. in no way affects the content of this declaration or my opinions
`
`in this matter.
`
`1
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`thereafter a Full Professor of Applied Biochemistry in the Department of Applied
`
`Biological Sciences (formerly the Department of Nutrition and Food Science) at
`
`M.I.T.
`
`3.
`
`I obtained my M.S. in Chemistry from Moscow University in Russia
`
`in 1971 and Ph.D. in Chemical Enzymology from the same University in 1974.
`
`Thereafter, I was a Research Chemist at Moscow University’s Department of
`
`Chemistry for three years. From 1977 to 1979, following my immigration to the
`
`United States, I was a Post-Doctoral Associate at the Department of Chemistry,
`
`University of California in San Diego.
`
`4.
`
`Over the last 45+ years as a practicing chemist, I have extensively
`
`researched, published, taught, and lectured in many areas of chemistry, including
`
`biological, medicinal, physical, bioorganic, formulation, and polymer.
`
`5.
`
`During my research career, I have earned numerous prestigious
`
`professional awards and honors. For example, I was elected to the U.S. National
`
`Academy of Sciences (considered among the highest honors that can be given to an
`
`American scientist) and also to the U.S. National Academy of Engineering
`
`(considered among the highest honors that can be given to an American engineer).
`
`I am also a Founding Fellow of the American Institute for Medical and Biological
`
`Engineering and a Corresponding Fellow of the Royal Society of Edinburgh
`
`(Scotland’s National Academy of Science and Letters). In addition, I have
`
`2
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`received the Arthur C. Cope Scholar Award (for achievements in organic
`
`chemistry), the Marvin J. Johnson Award (for achievements in biochemical
`
`technology), the Ipatieff Prize (for achievements in physical chemistry, particularly
`
`in catalysis), and the Leo Friend Award, all from the American Chemical Society,
`
`as well as the International Enzyme Engineering Prize.
`
`6.
`
`I have published over 310 scientific papers in various areas of
`
`chemistry and am also a named inventor of 21 issued United States patents and of
`
`many pending and foreign ones. I have given some 370 invited lectures (including
`
`a number of named lectures) at professional conferences, universities, and
`
`corporations all over the world, numerous of them dealing with formulation,
`
`solubility, stability, delivery, and biological evaluation of pharmaceutically active
`
`compounds.
`
`7.
`
`In addition to research and teaching at M.I.T., I have consulted widely
`
`for pharmaceutical, medical device, chemical, and biotechnology companies,
`
`including both innovator and generic pharmaceutical companies. I have also
`
`founded six pharmaceutical companies and have been on the scientific advisory
`
`boards and/or boards of directors of those companies and of many others. A
`
`number of these consulting, advisory, and directorship activities have dealt
`
`specifically with the formulation, chemical modification, solubility, stability,
`
`delivery, and biological evaluation of pharmaceutically active compounds, as well
`
`3
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`as their discovery and development.
`
`8.
`
`My curriculum vitae, which lists my professional experience and
`
`academic qualifications in greater detail, is attached hereto as Exhibit 2402.
`
`9.
`
`The time I spend working on this matter is being compensated at my
`
`current customary consulting rate of $950 per hour. This compensation does not
`
`monetarily benefit me personally but instead is credited directly to M.I.T. in order
`
`to financially support graduate students, postdoctoral associates, and scholarly
`
`activities. This compensation does not depend on, and is not affected by, the
`
`content of this expert declaration.
`
`II.
`
`ASSIGNMENT
`
`10.
`
`I understand that the Patent Trial and Appeal Board (the “Board”) of
`
`the United States Patent and Trademark Office issued a decision instituting inter
`
`partes review (“IPR”) of certain claims of U.S. Patent No. 5,665,772 (“the ’772
`
`Patent”) on the following grounds (the “Institution Decision”):
`
`Ground
`
`1
`
`2
`
`Challenged ‘772
`Patent Claims
`1-3, 10
`
`8, 9
`
`References
`Morris, Van Duyne, Rossmann,
`Yalkowsky, and Lemke
`Morris, Van Duyne, Rossmann,
`Yalkowsky, Lemke, and Hughes
`
`Basis
`
`§ 103(a)
`
`§ 103(a)
`
`(Paper 8 at 17-18.) I further understand that Novartis AG (“Novartis”) requested
`
`rehearing of the Board’s Institution Decision; however, the Board found that
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`4
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`Novartis’s request raised issues of fact and determined that the proceeding would
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`go forward. (Paper 21 at 4-6.) I have been asked by counsel for Novartis to
`
`provide my analysis and opinion on the validity of the ’772 Patent in light of
`
`certain opinions expressed in the Jorgensen declaration (Ex. 1003) and in the
`
`transcript of the August 9, 2016, Deposition of William L. Jorgensen (“Jorgensen
`
`Dep. Tr.”) (Ex. 2091), as well as certain arguments in Par’s Petition, the Board’s
`
`Institution Decision, and the Board’s decision denying Novartis’s request for
`
`rehearing (the “Rehearing Decision”) that are within my area of expertise.
`
`11. My analysis and opinions are based on studying the ’772 Patent, its
`
`file history, the Jorgensen declaration and documents cited therein, the Jorgensen
`
`deposition transcript, Par’s Petition, the Board’s Institution Decision, the Board’s
`
`Rehearing Decision, and the other documents referred to below, as well as my
`
`professional knowledge and experience.
`
`III.
`
`SUMMARY OF OPINIONS
`
`12. Grounds 1 and 2 rely on only two references, Lemke and Yalkowsky,
`
`to support the position that one of ordinary skill would have been motivated to
`
`chemically modify rapamycin to improve its water solubility by specifically
`
`inserting an ethyleneoxy (-CH2CH2O-) group at its C40 position to arrive at
`
`everolimus with a reasonable expectation that everolimus would have improved
`
`water solubility. This declaration explains why:
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`5
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`(a)
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`Lemke and Yalkowsky, the references that Par and Dr. Jorgensen rely
`
`on to select the specific modification to be made at rapamycin’s C40
`
`position (addition of an ethyleneoxy group) would not have led to, or
`
`taught, everolimus:
`
`(i)
`
`Lemke would have led one of ordinary skill to modify
`
`rapamycin with groups other than an ethyleneoxy group;
`
`(ii) Based on Lemke, one of ordinary skill would not have
`
`reasonably expected everolimus to have improved water
`
`solubility over rapamycin;
`
`(iii) Yalkowsky is not applicable here, as it concerns the ideal
`
`solubility of rigid molecules and their long-chain derivatives,
`
`but water is not an ideal solvent for rapamycin, and everolimus
`
`is not a long chain derivative; and
`
`(iv) According to Yalkowsky, the short-chain 2-hydroxyethyl ether
`
`C40 substituent of everolimus would not have been reasonably
`
`expected to improve rapamycin’s aqueous solubility.
`
`(b) More fundamentally, one of ordinary skill would not have considered
`
`rapamycin’s water solubility to be a problem that needed to be
`
`addressed.
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`(c)
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`Even if one of ordinary skill had been motivated to increase
`
`rapamycin’s water solubility, (s)he would have pursued approaches
`
`that (unlike everolimus) would have been reasonably expected to
`
`provide a meaningful increase in solubility, such as formulation,
`
`prodrug, or water-soluble salt approaches.
`
`IV. LEGAL PRINCIPLES
`
`Obviousness
`
`The following legal principles have been explained to me by counsel
`
`A.
`
`13.
`
`for Novartis.
`
`14. Claims 1-3 and 8-10 of the ’772 Patent are deemed “obvious” only if
`
`their subject matter, as a whole, would have been obvious to one of ordinary skill
`
`in the art as of October 9, 1992.2 In an IPR, the petitioner has the burden of
`
`proving that the challenged patent claims are obvious by a preponderance of the
`
`evidence—i.e., that the challenged claims are more likely obvious than not.
`
`15. Obviousness is assessed from the vantage point of one of ordinary
`
`skill in the field of the invention, and such factors as: (i) the education level of
`
`those working in the field, including the inventor(s) of the patent-in-suit; (ii) the
`
`2 Dr. Jorgensen also used the October 9, 1992, date for his analysis. (See Ex. 1003,
`
`Jorgensen Decl. ¶ 17; Ex. 2091, Jorgensen Dep. Tr. at 8:22 - 9:2, 9:14-21.)
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`7
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`sophistication of the technology; (iii) the types of problems encountered in the art;
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`(iv) the prior-art solutions to those problems; and (v) the speed at which
`
`innovations are made, help establish the level of ordinary skill in the art.
`
`16.
`
`The Board will determine whether an invention is obvious by
`
`assessing: (i) the level of ordinary skill in the art; (ii) the scope and content of the
`
`prior art; (iii) the differences between the prior art and subject matter claimed; and
`
`(iv) the existence of any objective evidence of non-obviousness.
`
`17.
`
`In determining the obviousness of new chemical compounds like
`
`everolimus in this case, the Board will consider whether one of ordinary skill in the
`
`art would have had a reason to select the asserted prior-art compound as a lead
`
`compound, or starting point, for further development and chemical modification.
`
`18.
`
`The Board will also consider whether the prior art would have
`
`supplied one of ordinary skill in the art with a reason or motivation to make the
`
`particular modification to the lead compound to result in the claimed compound
`
`and whether one of ordinary skill would have had a reasonable expectation of
`
`successfully achieving the result that prompted the modification. Furthermore, the
`
`motivation to modify a lead compound need not be explicit in the art.
`
`19. A prior-art reference must be considered in its entirety, including any
`
`portions that would lead away from the claimed invention. Failure to consider a
`
`prior-art reference as a whole is improper.
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`8
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`20.
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`Finally, it is improper in the obviousness analysis to use hindsight
`
`knowledge of the claimed compound itself.
`
`B.
`
`21.
`
`A Person Of Ordinary Skill In The Art
`
`I understand that the qualifications of a person of ordinary skill in the
`
`art here are assessed as of October 9, 1992, the date on which the GB ‘220 priority
`
`application was filed. As noted above, Dr. Jorgensen also uses the October 9,
`
`1992, date. (See Ex. 1003, Jorgensen Decl. ¶ 17; Ex. 2091, Jorgensen Dep. Tr. at
`
`8:22 - 9:2, 9:14-21.)
`
`22.
`
`In my opinion, a hypothetical person of ordinary skill in this art as of
`
`October 9, 1992, would have had a Ph.D. in medicinal or organic chemistry; or
`
`alternatively, a bachelor’s or master’s degree in medicinal or organic chemistry
`
`along with practical experience in the field. A person of ordinary skill in the art
`
`here would be working in the field of drug discovery together with individuals
`
`possessing knowledge and skills that (s)he might not possess through formal
`
`training or personal experience, including someone with experience in
`
`immunology, anti-tumor agents, and formulation development.
`
`9
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`V.
`
`GROUNDS 1 AND 2 ARE BASED ON THE ALLEGATION THAT
`ONE CLAIMED COMPOUND, EVEROLIMUS, IS OBVIOUS
`
`23.
`
`In Ground 1, Par contends that one of ordinary skill in the art would
`
`have selected rapamycin (structure below, left; Ex. 1003, Jorgensen Decl. ¶ 19) as
`
`a lead compound and had a motivation to increase its water solubility while
`
`retaining its immunosuppressive activity. (Pet. 16-17, 41-42; Ex. 1003, Jorgensen
`
`Decl. ¶¶ 138, 151.) Par further alleges that a person of ordinary skill would then
`
`rely on the combined teachings of four references, namely Van Duyne, Rossmann,
`
`Yalkowsky, and Lemke, to arrive at the compound everolimus (structure below,
`
`right; Ex. 1003, Jorgensen Decl. ¶ 38). (Pet. 10, 40).
`
`24.
`
`In particular, the Petition and the Jorgensen declaration argued that a
`
`person of ordinary skill would select rapamycin’s C40 carbon for chemical
`
`modification (based on the combined teachings of Van Duyne and Rossmann) and
`
`specifically would seek to replace rapamycin’s hydroxyl group at C40 with a
`
`10
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`“flexible” substituent (based on the teachings of Yalkowsky) having an alcohol,
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`amine, or carboxylic acid functional group (based on the teachings of Lemke).
`
`(Pet. 42-47; Ex. 1003, Jorgensen Decl. ¶¶ 141-155.) One of the three possible C40
`
`substituents that Par says a skilled artisan would investigate is the 2-hydroxyethyl
`
`ether (or 2-hydroxyethoxy, HOCH2CH2O-) group. (Pet. 47; Ex. 1003, Jorgensen
`
`Decl. ¶ 153.) The rapamycin derivative with this substituent at the C40 position
`
`(40-O-(2-hydroxyethyl)-rapamycin) is commonly known as everolimus.
`
`Everolimus is specifically claimed in claim 10 of the ’772 Patent. It is also
`
`covered by compound claims 1-3 of the ’772 Patent. (Pet. 11-12.)
`
`25.
`
`In Ground 2, which is directed to method of use claims 8 and 9 of the
`
`’772 Patent, Par relies on the same references as in Ground 1 plus the Hughes
`
`reference. Because claims 8 and 9 depend from claim 1, Par first must show that
`
`everolimus itself would have been obvious, before arguing that a method of using
`
`it would have been obvious.
`
`26.
`
`I understand that the Board instituted trial on Grounds 1 and 2 based
`
`on the arguments set forth in the Petition and the Jorgensen declaration. I also
`
`understand from his deposition testimony that Dr. Jorgensen is no longer pursuing
`
`many of the specific arguments set forth in his declaration and in the Petition with
`
`respect to Lemke and Yalkowsky. Instead, he now asserts that one of ordinary
`
`skill would rely on the combination of Lemke and Yalkowsky only for the general
`
`11
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`notion that flexible side chains containing nitrogen (N) or oxygen (O) atoms would
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`increase water solubility. Dr. Jorgensen further testified at his deposition that one
`
`of ordinary skill would disregard the other teachings in Lemke and Yalkowsky and
`
`would not use either reference to draw any quantitative conclusions about the
`
`expected water solubility of everolimus relative to that of rapamycin.
`
`27.
`
`For the reasons set forth below, under either the arguments set forth in
`
`Par’s papers or the new arguments advanced by Dr. Jorgensen at his deposition, I
`
`believe that everolimus would not have been obvious to a person of ordinary skill
`
`in the art as of October 9, 1992, because that person would have neither been
`
`motivated to make everolimus nor had a reasonable expectation that everolimus
`
`would achieve Par’s stated goals of retaining rapamycin’s immunosuppressive
`
`activity and having improved water solubility.
`
`28.
`
`In particular, this declaration addresses what I view as the critical
`
`flaws in Par’s and Dr. Jorgensen’s arguments on three key issues. First, I explain
`
`why Lemke and Yalkowsky would have neither motivated one of ordinary skill to
`
`increase rapamycin’s water solubility by making the specific chemical
`
`modifications required to produce everolimus nor provided a reasonable
`
`expectation that everolimus would have increased water solubility as compared to
`
`rapamycin. Second, I explain why Par’s references do not support the conclusion
`
`that one of ordinary skill would have considered rapamycin’s water solubility to be
`
`12
`
`NOVARTIS EXHIBIT 2092
`Par v Novartis, IPR 2016-00084
`Page 17 of 104
`
`
`
`a problem in need of a solution. And, finally, I explain why even if one of
`
`ordinary skill had been motivated to increase rapamycin’s water solubility (or
`
`improve its bioavailability), (s)he would have pursued alternative strategies, such
`
`as formulation, prodrug, or water-soluble salt approaches over the chemical
`
`modification that led to everolimus. All of my opinions apply equally to Grounds
`
`1 and 2, as both grounds rely on the same references for each of the water
`
`solubility issues addressed herein.
`
`29.
`
`In arriving at my opinions, I was asked by counsel for Novartis to
`
`assume that one of ordinary skill would have selected rapamycin as a lead
`
`compound and, if motivated to chemically modify rapamycin (an assumption I
`
`disagree with, as explained below), (s)he would have focused on modifications at
`
`the C40 position, rather than at other positions. I offer no opinions on whether
`
`these assumptions are consistent with the conclusions of one of ordinary skill in the
`
`art as of October 9, 1992.3
`
`3 I understand that Novartis’s expert, Dr. William R. Roush, will address these
`
`issues (among others).
`
`13
`
`NOVARTIS EXHIBIT 2092
`Par v Novartis, IPR 2016-00084
`Page 18 of 104
`
`
`
`VI. ONE OF ORDINARY SKILL SEEKING TO INCREASE
`RAPAMYCIN’S WATER SOLUBILITY WOULD NOT HAVE BEEN
`MOTIVATED TO SYNTHESIZE EVEROLIMUS OR HAD A
`REASONABLE EXPECTATION THAT IT WOULD HAVE
`INCREASED WATER SOLUBILITY
`
`A.
`
`Rapamycin And Everolimus Both Have An Alcohol Hydroxyl
`Functional Group At Their C40 Positions; However,
`Everolimus Has An Ether Oxygen And An Ethylene
`Group While Rapamycin Does Not
`
`30.
`
`To understand why Par’s challenge to claims 1-3 and 8-10 of the ’772
`
`Patent fails, let us consider the similarities and differences between the chemical
`
`structures of the prior-art compound rapamycin and of everolimus (i.e., 40-O-(2-
`
`hydroxyethyl)-rapamycin), the compound covered by compound claims 1-3 and 10
`
`and method of use claims 8 and 9 of the ’772 Patent. A person of ordinary skill in
`
`the art would have readily recognized these similarities and differences, which are
`
`beyond dispute. For convenience, only the relevant fragments of the chemical
`
`structures of rapamycin and everolimus are shown below, focusing on their
`
`respective carbon number 40 (C40) positions.
`
`14
`
`NOVARTIS EXHIBIT 2092
`Par v Novartis, IPR 2016-00084
`Page 19 of 104
`
`
`
`31. As shown above, at their C40 positions, rapamycin has an alcohol
`
`hydroxy (HO-) group and everolimus has a 2-hydroxyethyl ether (HOCH2CH2O-)
`
`group. Since both compounds have a single alcohol (HO-) functionality (shown
`
`in blue) as part of their C40 substituents, they do not differ in this respect. Said
`
`another way, both rapamycin and everolimus have a single alcohol hydroxyl (HO-)
`
`functional group attached directly or indirectly to their respective C40 carbon
`
`atoms. Thus, everolimus does not have any additional HO- functional groups
`
`compared to rapamycin. (Ex. 2091, Jorgensen Dep. Tr. at 126:24 - 127:5
`
`(confirming that rapamycin and everolimus have the same number of hydroxyl
`
`groups).)
`
`32. Rather, the atoms that differ between the two compounds’ C40
`
`substituents are indicated above in red: everolimus has an ether oxygen (-O-) and
`
`an ethylene (-CH2CH2-), whereas rapamycin has neither. Dr. Jorgensen, at his
`
`deposition, acknowledged that this is the difference between rapamycin and
`
`15
`
`NOVARTIS EXHIBIT 2092
`Par v Novartis, IPR 2016-00084
`Page 20 of 104
`
`
`
`everolimus. (Ex. 2091, Jorgensen Dep. Tr. at 126:16-23.) Below I explain why
`
`these similarities and differences in chemical structures are important.
`
`B.
`
`Lemke Does Not Provide A Motivation To Modify Rapamycin To
`Arrive At Everolimus, Nor A Reasonable Expectation
`That Everolimus Will Have Increased Water Solubility
`
`1.
`
`Par’s Reliance On Lemke Ignores The Undisputed
`Similarities And Differences Between The Chemical
`Structures Of Rapamycin And Everolimus
`
`33. Based on my reading of the Petition and the Jorgensen declaration,
`
`they relied exclusively on Lemke to argue that the addition of an alcohol hydroxyl
`
`functional group to rapamycin would be expected to improve its water solubility.
`
`(Pet. 23-24, 33-34, 45-47; Ex. 1003, Jorgensen Decl. ¶¶ 77, 82, 84, 88, 148, 149,
`
`153; Rehearing Decision at 4-5 (“Dr. Jorgensen testifies that a person of ordinary
`
`skill in the art would understand, based on Lemke, that alcohol, phenol, amine,
`
`carboxylic acid, ester, and amide groups would have the greatest solubilizing
`
`potential . . . . [H]e concluded that a person of ordinary skill in the art seeking to
`
`improve solubility would have had reason to modify rapamycin to add amino,
`
`hydroxyl, or carboxylate groups.”) (emphases added).)
`
`34. Before addressing the water solubility aspect of Lemke, it is important
`
`to stress that both the Petition and the Jorgensen declaration repeatedly suggested
`
`that the difference between rapamycin and everolimus was the addition of an
`
`alcohol group. (See, e.g., Ex. 1003, Jorgensen Decl. ¶¶ 77, 82, 84, 88, 148
`
`16
`
`NOVARTIS EXHIBIT 2092
`Par v Novartis, IPR 2016-00084
`Page 21 of 104
`
`
`
`(asserting that “Lemke teaches that the substituents with the most solubilizing
`
`potential are alcohol (hydroxyl), phenol, amines, carboxylic acid, ester and amide
`
`groups” (emphasis added)), 149, 153; Rehearing Decision at 4-5.) In fact, Par’s
`
`reliance on Lemke in its papers was based exclusively on the incorrect premise that
`
`everolimus has an additional hydroxyl group as compared to rapamycin. For
`
`example, the Petition stated that “Lemke teaches that the addition of various
`
`substituents ha[s] solubilizing potential.” (Pet. 45 (emphases added).) In
`
`particular, Par argued that Lemke teaches one of ordinary skill to modify
`
`rapamycin by “introduc[tion]” of the 2-hydroxyethyl ether side chain
`
`(HOCH2CH2O-) containing an alcohol (HO-) functional group. (Pet. 46-47, 52
`
`(emphasis added).) Likewise, Dr. Jorgensen stated that: (1) based on Lemke, one
`
`of ordinary skill “would have first selected alcohol (hydroxyl), amine, and lastly
`
`carboxylic acid groups with which to modify rapamycin to improve its solubility”
`
`(Ex. 1003, Jorgensen Decl. ¶ 149 (emphasis added)); and (2) Lemke would have
`
`taught a person of ordinary skill to “add . . . polar groups such as hydroxyl
`
`(alcohol), amino, and carboxylate groups” (Ex. 1003, Jorgensen Decl. ¶ 88
`
`(emphasis added); see also ¶¶ 152, 153).
`
`35. However, as explained above (see ¶¶ 30-32), it is evident and
`
`undisputed that rapamycin and everolimus have the same number of hydroxyl
`
`(alcohol) functional groups and do not differ by the “add[ition]” of any alcohol
`
`17
`
`NOVARTIS EXHIBIT 2092
`Par v Novartis, IPR 2016-00084
`Page 22 of 104
`
`
`
`functional groups. (Ex. 2091, Jorgensen Dep. Tr. at 126:24-127:5.) Indeed Dr.
`
`Jorgensen agreed at his deposition that the difference between rapamycin and
`
`everolimus is not the addition of a hydroxyl (alcohol) group but rather the insertion
`
`of an ether oxygen group and an ethylene (two carbons) group (together also called
`
`an “ethyleneoxy” group). (Ex. 2091, Jorgensen Dep. Tr. at 126:16-23.)
`
`36. Because the presence of an extra alcohol functional group is not a
`
`feature that distinguishes rapamycin from everolimus, one of ordinary skill who
`
`focused on Lemke’s teachings about adding hydroxyl groups would never arrive at
`
`everolimus. Par’s and Dr. Jorgensen’s arguments based on these teachings are
`
`hence misleading and do not support their position. To support its argument that a
`
`person of ordinary skill would have been led to everolimus, Par would have had to
`
`argue that Lemke taught that person to add the specific combination of oxygens
`
`and carbons that make up the actual difference between rapamycin and everolimus,
`
`i.e., the addition of an ether oxygen and an ethylene group. However, both the
`
`Petition and the Jorgensen declaration are silent on this issue and never suggest the
`
`addition of an ether oxygen and two carbons.
`
`37.
`
`Since the arguments in the Petition and the Jorgensen declaration with
`
`respect to Lemke (which are discussed in the Institution and Rehearing Decision)
`
`
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