UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`bioeq IP AG
`Petitioner
`
`v.
`
`Genentech, Inc.
`Patent Owner
`
`U.S. Patent No. 6,716,602
`_____________________
`
`Inter Partes Review Case No. Unassigned
`_____________________
`
`DECLARATION OF MORRIS Z. ROSENBERG, DSC.
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`BEQ 1002
`Page 1
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`Inter Partes Review of USPN 6,716,602
`Declaration of Morris Z. Rosenberg (BEQ 1002)
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`TABLE OF CONTENTS
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`B. 
`
`C. 
`
`Introduction ..................................................................................................... 1 
`I. 
`II.  My Background and Qualifications ................................................................ 2 
`III. 
`Summary of Opinions ..................................................................................... 4 
`IV.  List of Documents I Considered in Formulating My Opinions ..................... 7 
`V. 
`Person of Ordinary Skill in the Art ............................................................... 12 
`VI.  The '602 patent .............................................................................................. 13 
`VII.  Claim Construction ....................................................................................... 15 
`A. 
`"Increased yield of properly folded polypeptide" (claim 1). .............. 15 
`B. 
`"Culturing the recombinant host cells under conditions of
`high metabolic and growth rate" (claims 1, 25); "culturing
`host cells under conditions of high metabolic and growth
`rate" (claim 16). ................................................................................... 16 
`"Reducing the metabolic rate" (claims 1, 16, and 25). ........................ 17 
`C. 
`"Assembled" polypeptide (claims 11 and 35). .................................... 19 
`D. 
`VIII.  State of the Art Before November 3, 2000 ................................................... 20 
`A. 
`E. coli was "the most important" host for bacterial
`production of recombinant proteins as of 2000 .................................. 21 
`Excess glucose during bacterial fermentation was known to
`cause acetate accumulation—the main obstacle to obtaining
`high host cell densities and high protein production ........................... 23 
`Glucose-limited fed-batch fermentation minimized acetate
`accumulation and allowed to maximize bacterial cell mass
`and recombinant protein production ................................................... 25 
`Inducible
`promoters,
`such
`as
`phosphate-dependent
`promoters, were widely utilized for recombinant protein
`production ............................................................................................ 30 
`Recombinant antibody molecules and fragments were
`routinely produced in bacterial expression systems in 2000............... 33 
`IX.  Summary Chart of Analysis Over the Art .................................................... 46 
`X. 
`The Basis of my Analysis with Respect to Anticipation .............................. 46 
`A.  Ground 1: Seeger Discloses Every Limitation of Claims 1, 3,
`4, 6, 9, 15, 16, 20, 22, 24, 25, 27, 28, 30, 33, and 39 .......................... 47 
`1. 
`Claim 1. .................................................................................... 47 
`
`D. 
`
`E. 
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`BEQ 1002
`Page 2
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`Inter Partes Review of USPN 6,716,602
`Declaration of Morris Z. Rosenberg (BEQ 1002)
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`Claim 3. .................................................................................... 55 
`2. 
`Claim 4. .................................................................................... 56 
`3. 
`Claim 6. .................................................................................... 57 
`4. 
`Claim 9. .................................................................................... 59 
`5. 
`Claim 15. .................................................................................. 60 
`6. 
`Claim 16. .................................................................................. 62 
`7. 
`Claim 20. .................................................................................. 64 
`8. 
`Claim 22. .................................................................................. 65 
`9. 
`10.  Claim 24. .................................................................................. 67 
`11.  Claim 25. .................................................................................. 68 
`12.  Claim 27. .................................................................................. 70 
`13.  Claim 28. .................................................................................. 72 
`14.  Claim 30. .................................................................................. 73 
`15.  Claim 33. .................................................................................. 74 
`16.  Claim 39. .................................................................................. 75 
`XI.  The Basis of my Analysis with Respect to Obviousness ............................. 76 
`A.  Ground 2: Seeger, in view of general knowledge in the art,
`would have provided a reason to arrive at the method of
`claims 7, 8, 31, and 32 with a reasonable expectation of
`success ................................................................................................. 78 
`1. 
`Claim 7. .................................................................................... 78 
`2. 
`Claim 8. .................................................................................... 80 
`3. 
`Claim 31. .................................................................................. 81 
`4. 
`Claim 32. .................................................................................. 82 
`Ground 3: Seeger and Makrides Would Have Provided a
`Reason to Arrive at the Method of Claims 10, 12, 23, 34,
`and 36 with a Reasonable Expectation of Success ............................. 83 
`1. 
`Claim 10. .................................................................................. 83 
`2. 
`Claim 12. .................................................................................. 86 
`3. 
`Claim 23. .................................................................................. 89 
`4. 
`Claim 34. .................................................................................. 90 
`5. 
`Claim 36. .................................................................................. 91 
`Ground 4: Seeger and Cabilly would have Provided a
`Reason to Arrive at the Method of Claims 11, 13, 14, 18, 35,
`37, and 38 with a Reasonable Expectation of Success ....................... 92 
`1. 
`Claim 11. .................................................................................. 92 
`2. 
`Claim 13. .................................................................................. 95 
`3. 
`Claim 14. .................................................................................. 96 
`4. 
`Claim 18. .................................................................................. 97 
`
`B. 
`
`C. 
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`BEQ 1002
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`Inter Partes Review of USPN 6,716,602
`Declaration of Morris Z. Rosenberg (BEQ 1002)
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`D. 
`
`Claim 35. .................................................................................. 99 
`5. 
`Claim 37. ................................................................................ 100 
`6. 
`Claim 38. ................................................................................ 101 
`7. 
`Secondary Considerations of Non-obviousness ................................103 
`1. 
`No Unexpectedly Superior Results ........................................ 103 
`2. 
`No Long-Felt, Unmet Need ................................................... 107 
`3. 
`No Failure of Others .............................................................. 109 
`4. 
`No Industry Praise .................................................................. 110 
`XII.  Conclusion .................................................................................................. 111 
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`BEQ 1002
`Page 4
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`I, Morris Z. Rosenberg, DSc., hereby declare as follows.
`I.
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`Inter Partes Review of USPN 6,716,602
`Declaration of Morris Z. Rosenberg (BEQ 1002)
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`Introduction
`1.
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`I am over the age of eighteen and otherwise competent to make this
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`declaration.
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`2.
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`I have been retained as an expert witness on behalf of bioeq IP AG.
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`("bioeq") for the above-captioned inter partes review (IPR). I am being
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`compensated for my time in connection with this IPR at my standard consulting
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`rate, which is $475 per hour.
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`3.
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`I understand that the petition for inter partes review involves U.S.
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`Patent No. 6,671,602 ("the '602 patent"), BEQ1001, which resulted from U.S.
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`Patent Application No. 10/000,655 ("the '655 application"), filed November 1,
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`2001. I also understand that the '602 patent's earliest claimed priority date is
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`November 3, 2000, the filing date of U.S. Provisional Patent Application No.
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`60/245,962. The '602 patent names Dana Andersen, John Joly, and Bradley R.
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`Snedecor as the inventors. The '602 patent issued on April 6, 2004, from the '655
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`application. I understand that, according to the United States Patent and Trademark
`
`Office ("USPTO") records, the '602 patent is currently assigned to GENENTECH,
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`INC. ("GENENTECH").
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`4.
`
`The '602 patent is directed generally to the field of recombinant
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`polypeptide (protein) production, and more specifically to methods of increasing
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`BEQ 1002
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`product yield of a polypeptide produced by recombinant host cells, where
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`Inter Partes Review of USPN 6,716,602
`Declaration of Morris Z. Rosenberg (BEQ 1002)
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`expression of the polypeptide is regulated by an inducible system. BEQ1001, 1:
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`Abstract. The methods of the '602 patent involve culturing recombinant host cells
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`under conditions of high metabolic rate and high growth rate, and then reducing
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`the metabolic rate of the host cell at the time of induction of polypeptide
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`expression. Id. Metabolic rate is reduced by reducing the feed rate of a
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`carbon/energy source (e.g., glucose), or reducing the amount of available oxygen,
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`or both. BEQ1001, 4:23-27. According to the '602 patent, a decrease in metabolic
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`rate at the time of induction results in an increased yield of properly-folded
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`polypeptide. BEQ1001, 3:31-34.
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`5.
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`In preparing this Declaration, I have reviewed the '602 patent, the
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`prosecution history for the '602 patent, and each of the documents cited herein, in
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`light of general knowledge in the art. In formulating my opinions, I have relied
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`upon my experience, education, and knowledge in the relevant art. In formulating
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`my opinions, I have also considered the viewpoint of a person of ordinary skill in
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`the art ("POSA") (i.e., a person of ordinary skill in the field of recombinant protein
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`production defined further below in Section V) as of November 3, 2000.
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`II. My Background and Qualifications
`6.
`I am an expert in the field of recombinant polypeptide production, and
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`I have been an expert in this field since well before November 3, 2000. My
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`BEQ 1002
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`curriculum vitae is provided as BEQ1003. I obtained a Bachelor of Arts degree in
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`Inter Partes Review of USPN 6,716,602
`Declaration of Morris Z. Rosenberg (BEQ 1002)
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`Biology and a Bachelor of Science degree in Chemical Engineering from
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`Washington University, St. Louis, MO, in 1982. In 1985, I obtained a Master of
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`Science degree in Chemical Engineering, followed by a Doctor of Science degree
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`in 1989 from Washington University, St. Louis, MO.
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`7.
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`I worked as scientist and a marketing manager at Invitron
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`Corporation, St. Louis, MO, from 1987-1990. I subsequently worked as a Senior
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`Scientist and later as a Section Head of Biochemical and Process Engineering at
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`Biogen, Inc., Cambridge, MA, from 1990-1998. From 1998-2001, I was a Head of
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`Fermentation and Cell Culture Process Development at Eli Lilly & Company,
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`Indianapolis, IN. Subsequently, I served as an Executive Vice President of Process
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`Sciences at Seattle Genetics, Bothell, WA, from 2001-2012. I currently hold the
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`position of a President and the CEO at MRosenberg BioPharma Consulting, LLC.
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`8.
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`I have significant experience with production of recombinant proteins.
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`Specifically, I have specialized in developing E. coli fermentation processes for
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`various proteins, such as Teriparatide (Forteo), Bivalirudin 18-mer precursor
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`(Angiomax), and Glucagon-like peptide. I have experience in cellular and
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`molecular biology, fermentation, cell culture, bioreactor scale up, clarification,
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`analytical methods developments, analysis of production data, optimization of
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`fermentation processes, and production of Phase I/II cGMP supplies. I have
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`participated in the development and commercial launch of recombinant protein-
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`Inter Partes Review of USPN 6,716,602
`Declaration of Morris Z. Rosenberg (BEQ 1002)
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`based therapeutics such as Adcetrics®, Avonex®, Xigris®, Angiomax®, and
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`Forteo®.
`
`9.
`
`During my nearly 30 years of experience in the field of recombinant
`
`protein production, I have given numerous presentations and authored or co-
`
`authored a number of scientific articles. Each presentation and publication is listed
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`in my curriculum vitae, BEQ1003. Accordingly, I am an expert in the field of
`
`recombinant protein production.
`
`III. Summary of Opinions
`10.
`In this declaration, I consider methods for increasing yields of
`
`properly-folded recombinant protein of the '602 patent in relation to the state of the
`
`art before November 3, 2000. The prior art references that I considered when
`
`comparing the claims of the '602 patent to the state of the art include, but are not
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`limited to, Seeger (BEQ1010), Cabilly (BEQ1032), and Makrides (BEQ1023). I
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`also considered the file history of the '602 patent (BEQ1004).
`
`11. Claims 1, 3, 4, 6-16, 18, 20, 22-25, 27, 28, and 30-39 of the '602
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`patent are directed to methods for increasing yields of properly-folded recombinant
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`protein in a host cell. BEQ1001, 18:11-20:32. The methods comprise (a) culturing
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`the host cells under conditions of high metabolic and growth rate; and (b) reducing
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`the metabolic rate of the cultured host cells at the time of induction of polypeptide
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`BEQ 1002
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`expression, wherein reducing the metabolic rate comprises reducing the feed rate
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`Inter Partes Review of USPN 6,716,602
`Declaration of Morris Z. Rosenberg (BEQ 1002)
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`of a carbon/energy source, or reducing the amount of available oxygen, or both.
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`Id.
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`12. Claims 1, 3, 4, 6, 9, 15, 16, 20, 22, 24, 25, 27, 28, 30, 33, and 39 are
`
`anticipated by the prior art. Seeger discloses a method for producing recombinant
`
`polypeptide in E. coli, which method includes culturing cells at high metabolic and
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`growth rates, and reducing the metabolic rate of E. coli at the time of induction by
`
`reducing the feed rate of glucose (i.e., a carbon/energy source). BEQ1010,
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`Abstract, 948, Table 1, 948:2:1-3, 951:2:1, 952:2:1, and 953:1:1. Seeger further
`
`teaches that such a method increases expression of properly-folded polypeptide—
`
`the method results in an increased yield of soluble (i.e., properly-folded)
`
`polypeptide. Id., 952:2:2. It is also my opinion that the state of the prior art as of
`
`November 3, 2000 was well established with respect to methods of producing
`
`recombinant proteins, which would have allowed skilled artisans to practice the
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`method of Seeger without undue experimentation.
`
`13. Claims 7, 8, 31, and 32 would have been obvious in view of Seeger
`
`and in view of general knowledge in the art. It would have been within the general
`
`knowledge of a POSA to modify the method disclosed in Seeger, and i) to grow
`
`cell to maximum cell density prior to induction and ii) to reduce the metabolic rate
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`of the cells by about half. A POSA would have also had a reasonable expectation
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`of success in doing so because the field of recombinant protein production was
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`Inter Partes Review of USPN 6,716,602
`Declaration of Morris Z. Rosenberg (BEQ 1002)
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`well-developed and predictable as of 2000.
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`14. Claims 10, 12, 23, 34, and 36 would have been obvious in view of the
`
`prior art. A POSA would have routinely utilized a phosphate depletion inducible
`
`system, such as phoA, in the method disclosed by Seeger—the phoA promoter
`
`would have been one of the commonly used promoters. And a POSA would have
`
`had a reasonable expectation of success in doing so because the phoA promoter
`
`was generally known to be "applicable to the production of any of the categories of
`
`recombinant protein." BEQ1022, 5:2:2. A POSA would have also had a reason to
`
`use a system where recombinant polypeptides are secreted into the periplasm of E.
`
`coli, with a reasonable expectation of success in doing so, because Makrides
`
`provided multiple advantages of using such a system. BEQ1023, 520:2:3.
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`15. Claims 11, 13, 14, 18, 35, 37, and 38 would have also been obvious to
`
`a POSA in view of the prior art. A POSA would have had a reason to combine the
`
`teachings of Seeger and Cabilly to produce soluble and functional antibody
`
`fragments that are assembled in a host cell because both references addressed
`
`problems associated with low yields of protein expression and strategies for
`
`improving the same. A POSA would have also had a reasonable expectation of
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`success in doing so because Cabilly stated that the protocol was "relatively
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`simple," and it resulted in "about 100 ng" of functional polypeptide. BEQ1032,
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`Inter Partes Review of USPN 6,716,602
`Declaration of Morris Z. Rosenberg (BEQ 1002)
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`556:1:2.
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`16.
`
`In addition, I disagree with the arguments Genentech presented in the
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`file history of the '602 patent regarding unexpectedly superior results. First,
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`Genentech did not compare the claimed methods to the closest prior art—the
`
`claimed methods should have been compared with the method of Seeger, which
`
`employed a reduction in the metabolic rate to achieve superior protein yields.
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`Instead, Genentech compared the results achieved with the claimed methods with
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`the results from a method that did not include the metabolic rate reduction.
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`Second, the results obtained with the claimed methods are not superior: the results
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`do not represent a difference in kind, but merely in a degree. Third, the results
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`obtained with the claimed methods are not unexpected, as Seeger obtained
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`precisely the same result vis-à-vis an increased yield of properly-folded
`
`polypeptide.
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`17. Finally, I have not found any evidence that the claimed methods
`
`fulfilled a long-felt but unmet need or achieved any industry praise.
`
`IV. List of Documents I Considered in Formulating My Opinions
`18.
`In formulating my opinions, I have considered all the references and
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`documents cited herein, including those listed below.
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`Inter Partes Review of USPN 6,716,602
`Declaration of Morris Z. Rosenberg (BEQ 1002)
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`bioeq
`Exhibit #
`
`Description
`
`1001
`
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`1010
`
`1011
`
`Anderson, D., et al., "Metabolic Rate Shifts in Fermentations
`Expressing Recombinant Proteins," U.S. Patent No. 6,716,602 (filed
`November 1, 2001; issued on April 6, 2004)
`File History for U.S. Patent No. 6,716,602
`Knorre, W.A., et al., "High Cell Density Fermentation of
`Recombinant Escherichia coli with Computer-Controlled Optimal
`Growth Rate," Annals New York Academy of Sciences 646: 300-306
`(1991)
`Jackson, D.A., et al., "Biochemical Method for Inserting New
`Genetic Information into DNA of Simian Virus 40: Circular SV40
`DNA Molecules Containing Lambda Phage Genes and the
`Galactose Operon of Escherichia coli," Proceedings of the National
`Academy of Sciences 69(10): 2904-2909 (1972)
`Donovan, R.S., et al., "Review: Optimizing inducer and culture
`conditions for expression of foreign proteins under the control of the
`lac promoter," Journal of Industrial Microbiology 16: 145-154
`(1996)
`Korz, D.J., et al., "Simple fed-batch technique for high cell density
`cultivation of Escherichia coli," Journal of Biotechnology 39: 59-65
`(1995)
`Verma, R., et al., "Antibody engineering: Comparison of bacterial,
`yeast, insect, and mammalian expression systems," Journal of
`Immunological Methods 216: 165-181 (1998)
`Seeger, A. et al., "Comparison of temperature- and isopropyl-β-D-
`thiogalacto-pyranoside-induced synthesis of basic fibroblast growth
`factor in high-cell-density cultures of recombinant Escherichia
`coli," Enzyme and Microbial Technology 17: 947-953 (1995)
`Luli, G.W., et al., "Comparison of Growth, Acetate Production, and
`Acetate Inhibition of Escherichia coli Strains in Batch and Fed-
`Batch Fermentations," Applied and Environmental Microbiology
`56(4): 1004-1011 (1990)
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`Inter Partes Review of USPN 6,716,602
`Declaration of Morris Z. Rosenberg (BEQ 1002)
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`bioeq
`Exhibit #
`
`Description
`
`1012
`
`1013
`
`1014
`
`1015
`
`1016
`
`1017
`
`1018
`
`1019
`
`1020
`
`Akesson, M., et al., "A simplified probing controller for glucose
`feeding in Escherichia coli cultivations," Decision and Control 5:
`4520-4525 (2000)
`Strittmatter, W., et al., "Process for the Preparation of Recombinant
`Proteins in E. coli by High Cell Density Fermentation," U.S. Patent
`No. 6,410,270 (International Filing Date November 28, 1996; Issued
`June 25, 2002)
`Smirnova, G.V., et al., "Influence of Acetate on the Growth of
`Escherichia coli Under Aerobic and Anaerobic Conditions,"
`Mikrobiologiya 54(2): 205-209 (1985)
`Rinas, U., et al., "Glucose as a substrate in recombinant strain
`fermentation technology," Applied Microbiology and Biotechnology
`31: 163-167 (1989)
`CURRENT PROTOCOLS IN MOLECULAR BIOLOGY pp. 1.1.1- 1.15.8 and
`16.1-16.21 (Frederick M. Ausubel, et al., eds., Volume I,
`Supplement 3, 1995)
`Roszak, D.B., et al., "Survival Strategies of Bacteria in the Natural
`Environment," Microbiological Reviews 51(3): 365-379 (1987)
`Akesson, M., et al., "A probing feeding strategy for Escherichia coli
`cultures," Biotechnology Techniques 13: 523-528 (1999)
`Wangsa-Wirawan, N.D., et al., "Novel fed-batch strategy for the
`production of insulin-like growth factor 1 (IGF-1)," Biotechnology
`Letters 9(11): 1079-1082 (1997)
`Seeger, A. "Production of the Basic Fibroblast Growth Factor
`(bFGF) in a High Cell Density Process by means of Recombinant
`Escherichia coli," Dissertation submitted to the Department of
`Mechanical Engineering and Electrical Engineering of the Technical
`University of Carolo-Wilhelmina (1995)
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`Inter Partes Review of USPN 6,716,602
`Declaration of Morris Z. Rosenberg (BEQ 1002)
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`bioeq
`Exhibit #
`
`Description
`
`1021
`
`1022
`
`1023
`
`1024
`
`1025
`
`1026
`
`1027
`
`1028
`
`1029
`
`1030
`
`Lin, H., "Cellular responses to the induction of recombinant genes
`in Escherichia coli fed-batch cultures," Dissertation submitted to
`Martin-Luther-Universitat Halle-Wittenberg Faculty of Mathematics
`and Natural Sciences Department of Biochemistry and
`Biotechnology (2000)
`Sawers, G., et al., "Alternative regulation principles for the
`production of recombinant proteins in Escherichia coli," Applied
`Microbiology Technology 46: 1-9 (1996)
`Makrides, S.C., "Strategies for Achieving High-Level Expression of
`Genes in Escherichia coli," Microbiological Reviews 60(3): 512-538
`(1996)
`Wanner, B.L., "Gene Regulation by Phosphate in Enteric Bacteria,"
`Journal of Cellular Biochemistry 51: 47-54 (1993)
` UNDERSTANDING BIOLOGY pp. 117-139 (Burton S. Guttman and
`Johns W. Hopkins III, eds., 1983)
`Carter, P., et al., "High Level Escherichia coli Expression and
`Production of a Bivalent Humanized Antibody Fragment,"
`Biotechnology 10: 163-167 (1992)
`Better, M., et al., "Escherichia coli secretion of an active chimeric
`antibody fragment," Science 240: 1041 (1988)
`Shimuzu, N., et al., "Fed-Batch Cultures of Recombinant
`Escherichia coli with Inhibitory Substance Concentration
`Monitoring," Journal of Fermentation Technology 66: 187-191
`(1988)
`Bauer, K.A., et al., "Improved Expression of Human Interleukin-2
`in High-Cell-Density Fermentor Cultures of Escherichia coli K-12
`by a Phosphotransacetylase Mutant," Applied and Environmental
`Microbiology 56: 1296-1302 (1990)
`Huston, J.S., et al., " Protein engineering of antibody binding sites:
`recovery of specific activity in an anti-digoxin single-chain Fv
`analogue produced in Escherichia coli," Proceedings of the
`National Academy of Sciences 85: 5879 (1988)
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`Inter Partes Review of USPN 6,716,602
`Declaration of Morris Z. Rosenberg (BEQ 1002)
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`bioeq
`Exhibit #
`
`Description
`
`1031
`
`1032
`
`1033
`
`1034
`
`1035
`
`1036
`
`1037
`
`1038
`
`1039
`
`1040
`
`BIOPROCESS ENGINEERING PRINCIPLES pp. 257-296 (Pauline M.
`Doran, ed., 1995)
`Cabilly, S., "Growth at sub-optimal temperatures allows the
`production of functional, antigen-binding Fab fragments in
`Escherichia coli," Gene 85: 553-557 (1989)
`Boss, M.A., et al., "Assembly of functional antibodies from
`immunoglobulin heavy and light chains synthesized in E. coli,"
`Nucleic Acids Research 12:3791-3806 (1984)
`Cabilly, S., et al., "Generation of anyibody activity from
`immunoglobulin polypeptide chains produces in E. coli,"
`Proceedings of the National Academy of Sciences 81: 3273-3277
`(1984)
`Akesson, M., et al., "On-Line Detection of Acetate Formation in
`Escherichia coli Cultures Using Dissolved Oxygen Responses to
`Feed Transient," Biotechnology and Bioengineering 64: 590-598
`(1999)
`Hoffman, F., et al., "Minimizing inclusion body formation during
`recombinant protein production in Escherichia coli at bench and
`pilot plant scale," Enzyme and Microbial Technology 34: 235-241
`(2004)
`Jensen, E.B., et al., "Production of Recombinant Human Growth
`Hormone in Escherichia coli: Expression of Different Precursors
`and Physiological Effects of Glucose, Acetate, and Salts,"
`Biotechnology and Bioengineering 36: pp. 1-11 (1990)
`Turner, C., et al., "A Study of the Effect of Specific Growth Rate
`and Acetate on Recombinant Protein Production of Escherichia coli,
`JM107," Biotechnology Letters 16: 891-896 (1994)
`GENES III pp. 183-218 and 732 (Benjamin Lewin ed., Third Edition,
`1987)
`Qiu, J., et al., "Expression of Active Human Tissue-Type
`Plasminogen Activator in Escherichia coli," Applied and
`Environmental Microbiology 64: 4891-4896 (1998)
`
`- 11 -
`
`BEQ 1002
`Page 15
`
`

`
`
`
`
`
`bioeq
`Exhibit #
`
`Inter Partes Review of USPN 6,716,602
`Declaration of Morris Z. Rosenberg (BEQ 1002)
`
`Description
`
`1041
`
`1042
`
`1043
`
`1044
`
`1045
`
`1046
`
`1047
`
`Nan Chang, C., et al., "High-level secretion of human growth
`hormone by Escherichia coli," Gene 55: 189-196 (1987)
`Ulrich, H.D., et al., "Expression studies of catalytic antibodies,"
`Proceedings of the National Academy of Sciences 92: 11907-11911
`(1995)
`ESSENTIAL IMMUNOLOGY pp. 31-54 (Ivan Roitt ed., Sixth Edition,
`1988)
`Rosano, G.L., et al., "Recombinant protein expression in
`Escherichia coli: advances and challenges," Frontiers in
`Microbiology 5: pp. 1-17 (2014)
`Henry, N.G., "Effect of Decreasing Growth Temperature on Cell
`Yield of Escherichia coli," Journal of Bacteriology 98: 232-237
`(1969)
`Kovářová, K., et al., "Temperature-Dependent Growth Kinetics of
`Escherichia coli ML 30 in Glucose-Limited Continuous Culture,"
`Journal of Bacteriology 178: 4530-4539 (1996)
`Ko, Y.-F., et al., "A Metabolic Model of Cellular Energetics and
`Carbon Flux During Aerobic Escherichia coli Fermentation,"
`Biotechnology and Bioengineering 43: 847-855 (1994)
`
`V.
`
`
`Person of Ordinary Skill in the Art
`19.
`
`I understand that a person of ordinary skill in the art ("POSA") is a
`
`hypothetical person who is presumed to be aware of all pertinent art, thinks along
`
`conventional wisdom in the art, and is a person of ordinary creativity. I have
`
`reviewed the '602 patent claims and specification, and in my opinion, a POSA
`
`would typically have had a Ph.D. or a Doctor of Science (D.Sc.) and at least two
`
`years of experience, or an M.S. and at least four years of experience, in
`
`
`
`- 12 -
`
`BEQ 1002
`Page 16
`
`

`
`
`
`
`recombinant protein production, specializing in biochemistry, microbiology, or
`
`Inter Partes Review of USPN 6,716,602
`Declaration of Morris Z. Rosenberg (BEQ 1002)
`
`chemical engineering.
`
`20. A POSA typically would have worked as part of a multidisciplinary
`
`team and drawn upon not only his or her own skills, but also taken advantage of
`
`certain specialized skills of others in the team to solve a given problem. For
`
`example, such a team may be comprised of a chemical engineer, a microbiologist,
`
`a biochemist, and/or a molecular biologist. Before November 3, 2000, I personally
`
`worked on such multidisciplinary teams. As of November 3, 2000, the state of the
`
`art included the teachings provided by the references discussed in this declaration.
`
`Additionally, a POSA would have been aware of other important information and
`
`references relating to recombinant protein production and methods of producing
`
`recombinant polypeptides.
`
`VI. The '602 patent
`21.
`I understand that this declaration is being submitted together with a
`
`petition for inter partes review of claims 1, 3, 4, 6-16, 18, 20, 22-25, 27, 28, and
`
`30-39 of the '602 patent.
`
`22.
`
`I have considered the disclosure of the '602 patent in light of general
`
`knowledge in the art and the teachings of the scientific literature before the earliest
`
`possible priority date of the '602 patent, which I understand to be November 3,
`
`2000.
`
`
`
`- 13 -
`
`BEQ 1002
`Page 17
`
`

`
`
`
`
`
`Inter Partes Review of USPN 6,716,602
`Declaration of Morris Z. Rosenberg (BEQ 1002)
`
`23. The '602 patent is directed generally to the field of recombinant
`
`protein production, and more specifically to methods for increasing yields of
`
`properly-folded recombinant protein
`
`in a host cell. BEQ1001, Abstract.
`
`Independent claim 1 of the '602 patent is directed to a method for increasing
`
`product yield of a properly-folded polypeptide of interest in a host cell, which
`
`method comprises (a) culturing the host cells under conditions of high metabolic
`
`and growth rate; and (b) reducing the metabolic rate of the cultured host cells at the
`
`time of induction of polypeptide expression, wherein reducing the metabolic rate
`
`comprises reducing the feed rate of a carbon/energy source, or reducing the amount
`
`of available oxygen, or both. BEQ1001, 18:10-23. Dependent claims 2-15 add
`
`additional limitations to the method, such as specifying the carbon source or the
`
`host cell, limiting the method to a specific promoter, etc. BEQ1001, 18:24-56.
`
`Independent claims 16 and 25 recite methods similar to the methods of claim 1, but
`
`specify that the polypeptide of interest is an antibody, a growth factor, or a
`
`mammalian protease (claim 16) or a mammalian polypeptide (claim 25), and do
`
`not specify how the metabolic rate reduction is achieved. BEQ1001, 18:57-67 and
`
`19:20-32. Claims 17-24 depend from claim 16 and claims 26-39 depend from
`
`claim 25, and recite similar limitations to the limitations of claims 2-15.
`
`BEQ1001, 19:1-19, 19:29-34, and 20:1-32.
`
`
`
`- 14 -
`
`BEQ 1002
`Page 18
`
`

`
`
`
`
`VII. Claim Construction
`24.
`I understand that terms of the claims are to be given their broadest
`
`Inter Partes Review of USPN 6,716,602
`Declaration of Morris Z. Rosenberg (BEQ 1002)
`
`reasonable interpretation in light of the language of the claims and the specification
`
`of the '602 patent.
`
`A.
`"Increased yield of properly folded polypeptide" (claim 1).
`25. The '602 patent defines the term "product yield" as "the quantity of
`
`useful recombinant protein produced by a fermentation system." BEQ1001, 5:1-3.
`
`The specification further states that "[t]he independent control of [various] factors
`
`can lead to improved yields of usable products, such as for the case of soluble,
`
`properly folded and assembled antibody fragments." BEQ1001, 2:18-23. And: "the
`
`metabolic rate shift increases the yield of properly folded and, if appropriate,
`
`assembled protein. … In other words, we see significantly improved product yields
`
`by shifting the metabolic rate compared to the titers obtained by running the
`
`fermentation at a previously favorable, constant metabolic rate." Id., 3:20-23 and
`
`4:3-6. Thus, the specification compares protein yield from the claimed methods
`
`(i.e., with a meta