ViaEFS-Web
`July 24, 2009
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Applicant(s): Wayne R. Gombotz and Richard L. Remmele JR.
`
`Serial No.:
`
`11/784,538
`
`Group Ali Unit:
`
`1644
`
`Filed:
`
`For:
`
`April 6, 2007
`
`Examiner: OUSPENSKI, ILIA I
`
`POLYPEPTIDE FORMULATION
`
`Docket No.:
`
`3382-US-CNT
`
`RESPONSE TO OFFICE ACTION
`
`Mail Stop Amendment
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`Sir:
`
`This paper is filed in response to the Office Action dated April29, 2009.
`
`Submitted herewith are (1) a Declaration under 37 CFR 1.132 by Richard L. Remmele, Jr.,
`
`(2) a new Oath and/or Declaration, and (3) a Supplemental Information Disclosure Statement.
`
`• Amendments to the Specification begin on page 2 of this paper.
`
`• Amendments to the Claims begin on page 3 of this paper.
`
`• Remarks begin on page 6 of this paper.
`
`CERTIFICATE OF EFS-Web TRANSMISSION
`I hereby certifY that this paper (along with any referred to as being attached or enclosed) is being transmitted to the
`United States Patent and Trademark Office via EFS-Web on the date indicated below:
`____ ....,..L:,:;:;;;;>~;=9=-::::::==::::._---
`July 24, 2009
`••... <:C:;::;ra;&f"""
`Date
`
`Ex. 2015-0001
`
`

`

`USSN 11/784,53 8
`Response to First Office Action
`July 24, 2009
`
`Immunex Corporation
`3382-US-CNT
`
`Amendments to the Specification
`
`Please replace the title of the specification at the top of page 1 with the following new title:
`
`POLYPEPTIDE FORMULl'JIONStable Aqueous Formulation of a Soluble TNF Receptor
`
`and Arginine
`
`2
`
`Ex. 2015-0002
`
`

`

`USSN 11/784,538
`Response to First Office Action
`July 24, 2009
`
`Amendments to the Claims
`
`hnmunex Corporation
`3382-US-CNT
`
`The listing of claims will replace all prior versions, and listings, of claims in the
`
`application:
`
`(Claims 1-56 are cancelled.)
`
`57.
`
`(New) A pharmaceutical composition that is a stable aqueous formulation
`
`comprising a polypeptide that is an extracellular ligand-binding portion of a human p75 tumor
`
`necrosis factor receptor fused to the Fe region of a human IgG 1 and an aggregation inhibitor,
`
`wherein the aggregation inhibitor is L-arginine at a concentration of from about 10 mM to
`
`about 200mM.
`
`58.
`
`(New) The composition of claim 57, further comprising a buffer.
`
`59.
`
`(New) The composition of claim 58, wherein the buffer is selected from the
`
`group consisting of sodium phosphate, histidine, potassium phosphate, sodium or potassium
`
`citrate, maleic acid, ammonium acetate, tris-(hydroxymethyl)-aminomethane (tris), acetate
`
`and diethanolamine.
`
`60.
`
`(New) The composition of claim 59, wherein the L-arginine is at a
`
`concentration of from about 10 mM to about 75 mM.
`
`61.
`
`(New) The composition of claim 60, further comprising a tonicity modifier.
`
`62.
`
`(New) The composition of claim 61, wherein the tonicity modifier is selected
`
`from the group consisting of arginine, cysteine, histidine, glycine, sodium chloride, potassium
`
`chloride, sodium citrate, sucrose, glucose and mannitol.
`
`63.
`
`(New) The composition of claim 62, wherein the tonicity modifier is sodium
`
`chloride.
`
`64.
`
`(New) The composition of claim 57, further comprising an excipient.
`
`3
`
`Ex. 2015-0003
`
`

`

`USSN 11/784,538
`Response to First Office Action
`July 24, 2009
`
`Immunex Corporation
`3382-US-CNT
`
`65.
`
`(New) The composition of claim 63, further comprising an excipient.
`
`66.
`
`(New) The composition of claim 64 wherein the excipient is selected from the
`
`group consisting of sucrose, lactose, glycerol, xylitol, sorbitol, Mannitol, maltose, inositol,
`
`trehalose, glucose, bovine serum albumin (BSA), human SA or recombinant HA, dextran,
`
`PV A, hydroxypropyl methylcellulose (HPMC), polyethyleneimine, gelatin,
`
`polyvinylpyrrolidone (PVP), hydroxyethylcellulose (HEC), polyethylene glycol, ethylene
`
`glycol, glycerol, dimethysulfoxide (DMSO), dimethylfonnamide (DMF), proline, L-serine,
`
`sodium glutamic acid, alanine, glycine, lysine hydrochloride, sarcosine, gamma-aminobutyric
`
`acid, Tween-20, Tween-80, SDS, polysorbate, polyoxyethylene copolymer, potassium
`
`phosphate, sodium acetate, ammonium sulfate, magnesium sulfate, sodium sulfate,
`
`trimethylamine N-oxide, betaine, zinc ions, copper ions, calcium ions, manganese ions,
`
`magnesium ions, CHAPS, sucrose monolaurate, and 2-0-beta-mannoglycerate.
`
`67.
`
`(New) The composition of claim 66, wherein the excipient is sucrose.
`
`68.
`
`(New) A stable pharmaceutical composition comprising from about 10 mg/ml
`
`to about 1 00 mg/ml etanercept, and further comprising L-arginine, sodium phosphate, sodium
`
`chloride and sucrose.
`
`69.
`
`(New) The composition of claim 68, wherein the L-arginine is at a
`
`concentration of from about 10 mM to about 75 mM.
`
`70.
`
`(New) The composition of claim 68, wherein the sodium phosphate is at a
`
`concentration of from about 5 mM to about 100 mM.
`
`71.
`
`(New) The composition of claim 68, wherein the sodium chloride is at a
`
`concentration of from about 5 mM to about 200 mM.
`
`72.
`
`(New) The composition of claim 68, wherein the sucrose is at a concentration
`
`of from about 0.5% to about 1.5%.
`
`73.
`
`(New) The composition of claim 68, wherein the pH of the composition is
`
`from about 5.5 to about 7.8.
`
`4
`
`Ex. 2015-0004
`
`

`

`USSN 11/784,538
`Response to First Office Action
`July 24, 2009
`
`Immunex Corporation
`3382-US-CNT
`
`74.
`
`(New) The composition of claim 68, comprising fi·om 25 to 50 mg/ml
`
`etanercept, about 25 mM L-arginine, about 25 mM sodium phosphate, about 100 mM sodium
`
`chloride, about 1% sucrose, and at about pH 6.0 to about pH 7.0.
`
`75.
`
`· (New) The composition of claim 74, further comprising polysorbate 20.
`
`76.
`
`(New) The composition of claim 74, wherein the composition is in a fi·ozen
`
`state.
`
`77.
`
`(New) A method of formulating a composition comprising combining an
`
`isolated polypeptide that is an extracellular ligand-binding portion of a human p75 tumor
`
`necrosis factor receptor fused to the Fe region of a human IgG1 with L-arginine at a
`
`concentration of from about 10 mM to about 200mM.
`
`78.
`
`(New) The method of claim 77, further comprising the steps of combining a
`
`buffer, a tonicity modifier, and an excipient with the composition.
`
`79.
`
`(New) The method of claim 78, wherein the buffer is sodium phosphate, the
`
`tonicity modifier is sodium chloride at a concentration of from 5 mM to 200 mM, and the
`
`exipient is sucrose at a concentration of from 0.5% to 1.5%.
`
`80.
`
`(New) The method of claim 79, further comprising adding polysorbate 20.
`
`81.
`
`(New) The method of claim 77, futiher comprising freezing the composition.
`
`82.
`
`(New) The method of claim 79, further comprising freezing the composition.
`
`5
`
`Ex. 2015-0005
`
`

`

`USSN 11/784,538
`Response to First Office Action
`July 24, 2009
`
`Immunex Corporation
`3382-US-CNT
`
`REMARKS
`
`Claims 1, 33, 36-46, and 49-55 have been cancelled by this amendment, and replaced
`
`by new Claims 57-82. The new claims more precisely define the claimed invention, and
`
`present no new matter issues. The claims are fully supported throughout the application as
`
`originally filed. Exemplary citations for suppmi are in the following table.
`
`Claim No.
`
`Suppmi in Specification as Filed
`
`57
`
`58
`
`59
`
`60
`
`61
`
`62
`
`63
`
`64
`
`65
`
`66
`
`67
`
`68
`
`69
`
`70
`
`71
`
`72
`
`73
`
`74
`
`75
`
`76
`
`77
`
`78
`
`79
`
`80
`
`81
`
`82
`
`Claim 1; p. 4, ln. 20-26; page 9, ln. 12
`
`Claim 2
`
`Claim 3
`
`Claim 4, p. 9, ln. 11-14
`
`Claim 5
`
`Claim 6
`
`Claim 7
`
`Claim 8
`
`Claim 10
`
`Claim 11
`
`Claim 12
`
`Claim 13
`
`Claim 14, p. 9, ln. 11-14
`
`Claim 15
`
`Claim 16
`
`Claim 17
`
`Claim 18
`
`Claim 19, p. 10, ln. 33 top. 11, ln. 7
`
`p. 10, ln. 23
`
`Claim 21
`
`Claim 22
`
`Claim23
`
`Claims 23, 16, and 17
`
`p. 10, ln. 23
`
`Claim 21
`
`Claim 21
`
`6
`
`Ex. 2015-0006
`
`

`

`USSN 11/784,538
`Response to First Office Action
`July 24, 2009
`
`The Oath or Declaration
`
`Immunex Corporation
`3382-US-CNT
`
`The Examiner noted that the Oath or Declaration was defective in that it did not
`
`identify the citizenship of each inventor. Applicants enclose herewith a newly executed Oath
`
`or Declaration.
`
`The Title of the Invention
`
`The Examiner asserts that a new title is required that is clearly indicative of the
`
`invention to which the claims are directed. Applicants have changed the title to read "Stable
`
`Aqueous Formulation of a Soluble TNF Receptor and Arginine," which clearly indicates the
`
`invention to which the claimed are directed.
`
`35 U.S.C. 103(a)'
`
`Claims 1, 33, 36-46, and 49-55 are rejected under 35 U.S.C. 103(a) as allegedly
`
`unpatentable over Kakuta et al. (US Patent Application No. 2003/0190316) in view of Chen
`
`eta!. (US Patent Application No. 2003/0180253), and further in view ofMoreland et al.
`
`(Ann. Intern. Med. 1999; 130: 478-486).
`
`The Examiner asserts that Kakuta et al. teach that pharmaceutical compositions
`
`containing antibodies are stabilized in formulations with L-arginine (citing paragraph 0084
`
`and 0085), 200 mM sodium chloride, 19 mM sodium phosphate (citing paragraph 0071),
`
`0.05-lM sucrose (citing paragraph 75), and with pH 5 to 8 (citing paragraph 0076). Chen et
`
`al. is cited for describing stabilizing liquid polypeptide-containing pharmaceutical
`
`compositions by using a variety of chemicals including L-arginine at concentrations of20-150
`
`mM (citing in particular page 2 and Figure 9), as well as liquid and frozen states. Moreland
`
`et a!. is cited for teaching the use of etanercept to treat rheumatoid mihritis. The Examiner
`
`states that one of ordinary skill would be motivated to prepare a stable aqueous injectable
`
`solution of etanercept, and have a reasonable expectation of success because optimization of
`
`stable aqueous solutions of polypeptides comprising the recited components were routine in
`
`the mi at the time the invention was made, as evidenced by Kakuta et al. and Chen et al.
`
`This rejection is respectfully traversed. Section 103 requires consideration of whether
`
`the claimed invention as a whole would have been obvious to one of ordinary skill in the mi
`
`at the time the invention was made, taking into consideration (1) the scope and content of the
`
`prior art; (2) the differences between the prior mi and the claims at issue; (3) the level of
`
`ordinary skill in the pertinent art; and (4) any relevant secondary indicia of non-obviousness.
`
`See 35 U.S.C. §103(a); see also KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1734 (2007)
`
`7
`
`Ex. 2015-0007
`
`

`

`USSN 11/784,538
`Response to First Office Action
`July 24, 2009
`
`lmmunex Corporation
`3382-US-CNT
`
`(quoting Graham v. John Deere Co. of Kansas City, 383 U.S. 1, 17-18 (1966)). Here, the
`
`claims at issue relate to a pharmaceutical composition that is a stable aqueous formulation
`
`comprising a polypeptide that is an extracellular ligand-binding portion of a human p75 tumor
`
`necrosis factor receptor fused to the Fe region of a human IgG 1 and L-arginine at a
`
`concentration of from about 10 mM to about 200mM as aggregation inhibitor. In particular
`
`embodiments, the claims relate to stable pharmaceutical composition comprising from about
`
`10 mg/ml to about 100 mg/ml etanercept, L-arginine, sodium phosphate, sodium chloride and
`
`sucrose. However, the cited art, taken together, does not teach the claimed invention, nor
`
`would there be any reasonable expectation of success in achieving the claimed invention.
`
`The Art is Unpredictable
`
`Contrary to the basis for the rejection, optimization of stable liquid pharmaceutical
`
`compositions of polypeptides is not routine. Proteins, as opposed to small molecule drugs,
`
`are large and complex molecules. Different proteins have different charaCteristics that affect
`
`their stability, folding, solvent interaction, hydrophobicity, and degradation pathways. The
`
`challenges of protein formulation are well recognized in the art. For example, the Examiner's
`
`attention is directed to a review article, Wang, W. (1999) lnternatl. J. Pharmaceutics 185:
`
`129-188, submitted as reference C8 in the Information Disclosure Statement filed April 9,
`
`2007. Wang explains that "the structural differences among different proteins are so
`
`significant that generalization of universal stabilization strategies has not been successful."
`
`Wang at p. 130. After reviewing the literature on assessment of protein stability and the
`
`many different parameters and possibilities that can affect the same, Wang concludes by
`
`stating that "the most formidable challenge in formulating a liquid protein pharmaceutical is
`
`to preserve the biological activity of the protein for an acceptable shelf life. Unfortunately,
`
`there is no single pathway to follow in formulating such a product." Wang at p. 178.
`
`The declaratory evidence submitted herewith further supports the lack of reasonable
`
`expectation of success in reaching a stable aqueous formulation. In particular, Dr. Remmele
`
`opines that simply because an excipient stabilizes one protein, does not predict that it will
`
`stabilize another. Dr. Remmele points to additional support in the literature, where even
`
`antibodies, which as a class can share distinct structural similarities, will respond differently
`
`in solution (see paragraphs 3 and 4 of the Declaration under 37 CPR 1.132 by Richard L.
`
`Remmele, Jr.). Accordingly, even proteins from the same class, antibodies, respond
`
`differently and unpredictably to formulation in solution.
`
`8
`
`Ex. 2015-0008
`
`

`

`USSN 11/784,538
`Response to First Office Action
`July 24, 2009
`
`hnmunex Corporation
`3382-US-CNT
`
`The Cited Art Does Not Teach the Claimed Combinations
`
`Turning to the cited references, Applicants submit that taken together they do not
`
`teach the optimization of the currently claimed formulations. In particular, the art does not
`
`teach or suggest a combination of an extracellular ligand-binding portion of a human p75
`
`tumor necrosis factor receptor fused to the Fe region of a human IgG 1 and L-arginine at a
`
`concentration of from about 10 mM to about 200mM as aggregation inhibitor. Nor does the
`
`art teach the combination of any protein with arginine, sodium phosphate, sodium chloride,
`
`and sucrose.
`
`Chen et al. teaches formulations of either IL-2 or TFPI with 20-150 mM arginine in
`
`combination with succinate compounds. Chen does not teach etanercept, nor does Chen
`
`teach other additions such as sodium phosphate, sodium chloride, sucrose. However, the
`
`Office asserts that Kakuta et al. teaches pharmaceutical compositions containing antibodies
`
`are stabilized in formulations with L-arginine, 200 mM sodium chloride, 19 mM sodium
`
`phosphate, 0.05-lM sucrose, and with pH 5 to 8. Careful reading ofthe paragraphs cited by
`
`the Office Action reveals that the formulation described in paragraph 71 is an undesired
`
`formulation of phosphate and NaCl which aggregated above 70° C. In paragraph 72, the
`
`authors disclose that they overcame the problem described in paragraph 71 by using glycine
`
`and/or histidine buffers. They do not combine these buffers with the buffered formulation in
`
`paragraph 71. Paragraph 73 and paragraph 74 go on to describe more desired details of their
`
`histidine and/or glycine buffers. Paragraph 75, which was combined by the Examiner with
`
`paragraph 71, teaches that one should not use the NaCl with the histidine and/or glycine
`
`buffer because it lowers the aggregation reducing effect of glycine and/or sucrose.
`
`(Applicants note for the record that Kakuta et al. describes use of sodium chloride at
`
`paragraph [0095].)
`
`These teachings appear to be based upon the experimental section of the application
`
`disclosure. In particular, the composition in paragraph 71 was tested in Example 1
`
`(paragraphs 114 and 115), and found to be lacking. The authors then tested a variety of
`
`buffers in Example 2. Example 2 concludes with the disclosure that addition of 50 mM NaCl
`
`to any of the buffers in Example 2 resulted in greatly increased aggregation. It should be
`
`noted, in none of the working examples is arginine used as an aggregation inhibitor or
`
`stabilizer, or even to titrate buffer. Even if arginine was used to titrate the histidine and/or
`
`glycine buffer, Kakuta teaches against combining that arginine/histidine or glycine solution
`
`with NaCl. "[W]hen the prior art teaches away from combining certain known elements,
`
`discovery of a successful means of combining them is more likely to be nonobvious." KSR
`
`9
`
`Ex. 2015-0009
`
`

`

`USSN 11/784,538
`Response to First Office Action
`July 24, 2009
`
`Immunex Corporation
`3382-US-CNT
`
`Int'l Co. v. Teleflex Inc., 550 U.S._, 127 S. Ct. 1727, 1740, 82 U.S.P.Q.2d 1385, 1395
`
`(2007), citing United States v. Adams, 383 U.S. 39, 51-52, 86 S. Ct. 708, 714-715 (1966).
`
`Thus, contrary to the Examiner's assertion, the reference Kakuta does not teach the
`
`combination alleged by the Examiner. The Examiner has impermissibly combined individual
`
`pmts of paragraphs without regard to what the paragraphs actually teach. A reference is
`
`available for all that it teaches, and it is improper to pick and choose among the disclosure,
`
`ignoring that which contradicts the basis of the rejection and which indicates that the
`
`combination alleged to be taught is not in fact taught.
`
`The effect of arginine as an excipient in a liquid formulation is unpredictable
`
`Regardless of the deficiencies of the combinations relied upon to support the present
`
`rejection, Applicants submit that any expectation of success cannot be assumed when
`
`developing liquid protein formulation. This is patticularly true with respect to the presently
`
`claimed invention, which relates to the use of arginine in a stable aqueous formulation of a
`
`human p75 tumor necrosis factor receptor fused to the Fe region of a human IgGl, and the
`
`commercially available embodiment etanercept. First of all, the formulation comprises a
`
`recombinant fusion protein with a non-naturally occurring primary, secondary, and tertiary
`
`structure. Second of all, there are a vast number of different formulation approaches that
`
`could be taken in attempting to achieve a stable aqueous composition, as evidenced by Wang,
`
`W. (1999) Internatl. J. Pharmaceutics 185: 129-188 (discussed above). There is no specific
`
`guidance for determining how to arrive at a stable formulation of such a fusion protein.
`
`Although Chen et al. teaches to use arginine/succinate formulations of two rather small
`
`proteins, the literature is replete with repmts that arginine destabilizes proteins. As noted by
`
`Dr. Remmele in paragraph 6 of his declaration, Rishi et al., Biochem. J. v. 329:137-143
`
`(1998) discuss the effect of arginine, histidine, and lysine on the stabilization of several
`
`different proteins against thermal denaturation. Rishi et al. state that arginine appears to bind
`
`to denatured molecules and destabilized the five different tested proteins when tested using
`
`thermal denaturation.
`
`"A court must ask whether the improvement is more than the predictable use of prior(cid:173)
`
`art elements according to their established functions." KSR Intern. Co. v. Teleflex Inc. 550
`
`U.S. 398, 82, 127 S. Ct. 1727, 1731, 82 USPQ2d 1385 (2007). In this case, the use of
`
`arginine is well established by the prior art to be unpredictable, indeed, even destabilizing.
`
`Thus, the use ofL-arginine to form a stable pharmaceutical composition of a human p75
`
`tumor necrosis factor receptor fused to the Fe region of a human IgG 1 is not at all predictable,
`
`and certainly not its established function.
`
`10
`
`Ex. 2015-0010
`
`

`

`USSN 11/784,538
`Response to First Office Action
`July 24, 2009
`
`hnmunex Corporation
`3382-US-CNT
`
`Fmihermore, the use of arginine as an aggregation inhibitor gave unexpectedly better
`
`results than other excipients in achieving a stable aqueous formulation of a human p75 tumor
`
`necrosis factor receptor fused to the Fe region of a human IgG 1. Dr. Remmele notes at
`
`paragraphs 7 through 9 of his declaration that he tested a number of different excipients, and
`
`the results with arginine were unexpectedly and dramatically better than other excipients. It
`
`should be noted that one of the excipients tested in this experiment was glycine (see
`
`paragraph 8 and Exhibit D to the Declaration under 37 CFR 1.132 by Richard L. Remmele,
`
`Jr.). Glycine was not nearly as good as arginine at stabilizing the protein solution against
`
`aggregation. If one were to rely upon the Kakuta et al. to predict stabilizing activity, glycine
`
`should have been a stabilizing additive, but it was not. This surprising result with arginine
`
`further evidences the non-obviousness of the claimed pharmaceutical compositions.
`
`In conclusion, the art recognizes that results with one protein in achieving a stable
`
`aqueous formulation cannot be extrapolated to other proteins. The instant claims are
`
`narrowly drawn to a pharmaceutical composition comprising the species of a particular fusion
`
`protein, a human p 7 5 tumor necrosis factor receptor fused to the F c region of a human IgG 1,
`
`and/or to the version of this molecule is known as etanercept. There was no reasonable
`
`expectation ofsuccess in applying pieces and various combinations of the prior art with other
`
`proteins to achieve the currently claimed invention. The Office, in asserting the species
`
`election requirement on October 2, 2008, implicitly recognized the limitations of applying art
`
`based on formulations of one protein to a completely different type of protein. In particular,
`
`the requirement for the species election was based on the individual species' mutually
`
`exclusive characteristics. The Office assetied that the species require a different field of
`
`search; and/or the prior mi applicable to one species would not likely be applicable to another
`
`species; and/or the species are likely to raise different non-prior mi issues under 3 5 USC 101
`
`and/or 35 USC 112. See page 4 of the paper mailed October 2, 2008. Applicants did not
`
`traverse these assetiions because they agree that prior art with one of the non-elected species
`
`would not be applicable to another, and that enablement of a stable aqueous formulation of
`
`one protein does not necessarily enable another. Applicants submit that withdrawal of the
`
`rejection under 35 USC 1 03(a) would be consistent with the prior assertions by the Office.
`
`In view ofthe unpredictability in the mi, the lack of specific guidance, the teaching
`
`away of certain combinations, and the evidence submitted herewith, Applicants request
`
`reconsideration and withdrawal ofthe remaining rejection under 35 USC 103(a).
`
`11
`
`Ex. 2015-0011
`
`

`

`USSN 11/784,538
`Response to First Office Action
`July 24, 2009
`
`Immunex Corporation
`3382-US-CNT
`
`CONCLUSION
`A favorable action is respectfully requested. Should the Examiner believe that any
`issues could be resolved by way of a teleconference, the Examiner is invited to telephone the
`undersigned representative of the Applicants, to discuss resolution thereof.
`
`Kathleen Fowler
`Attorney/Agent for Applicant(s)
`Registration No.: 40,611
`Phone: (206) 265-7847
`Date:
`July 24, 2009
`
`Please send all future correspondence to:
`22932
`Immunex Corporation
`Law Department
`1201 Amgen Comt West
`Seattle, WA 98119-3105
`(206) 265-7000
`
`12
`
`Ex. 2015-0012
`
`

`

`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`PATENT APPLICATION
`
`Applicant( s): Gombotz and Remmele
`
`Serial No.:
`
`11/784,538
`
`Group Art Unit
`No.:
`
`1644
`
`Filed:
`
`April 6, 2007
`
`Examiner: Ouspenski, Ilia I
`
`For:
`
`Polypeptide Formulation
`
`Docket No.: 3382-US-CNT
`
`DECLARATION UNDER 37 CFR 1.132
`
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`Sir:
`
`I, Richard L. Remmele, Jr., declare that:
`
`1. I am currently a Scientific Director in the Analytical and Formulation Sciences Group
`at Amgen Inc., where I have been employed since July 2002. Previously, I was a Staff Scientist
`and later promoted to Sr. Staff Scientist in my employment for nine years at Immunex
`Corporation. I have been working in the field of protein formulation for more than fifteen years.
`I am also a co-inventor of the invention claimed in the above-captioned patent application. I am
`informed that a copy of the claims as they will be amended is attached as Exhibit A.
`
`2. Different classes of proteins differ greatly from each other, and different proteins react
`in different ways. Proteins can be, for example, hydrophobic or hydrophilic, monomeric or
`oligomeric, and their primary and secondary structures give them a wide variety of chemical
`actions.
`
`3. In my experience, one cannot expect that an excipient that stabilizes one protein will
`predictably stabilize another protein. In other words, there is no universal stabilizer for liquid
`formulations of pharmaceutical proteins.
`
`Ex. 2015-0013
`
`

`

`DECLARATION OF RICHARD L. REMMELE, JR.
`
`4. This fact is recognized in the art. Wang et al., J. ofPharm Sc., v. 96(1):1-26 (2007), is
`a Minireview entitled "Antibody Structure, Instability, and Formulation," a copy of which is
`attached as Exhibit B. The authors state that "[a]lthough antibodies share certain structural
`similarities, development of commercially viable antibody pharmaceuticals has not been
`straightforward because of their unique and somewhat unpredictable solution behavior." (See
`Abstract.)
`
`5. I understand that the Office has asserted that Kakuta et al. teach that pharmaceutical
`compositions containing antibodies are stabilized in formulations with L-arginine. I interpret
`Kakuta et al. differently. Kakuta et al. teach that stabilized preparations of antibodies can be
`prepared by dissolving an antibody in a glycine buffer and/or a histidine buffer (see paragraph
`0073). However, Kakuta et al. does not teach to use arginine to stabilize a protein preparation.
`Instead, Kakuta et al. merely describes that one should adjust the pH of the glycine or histidine
`buffer with a basic amino acid such as arginine (see paragraph 0078 and 0074) rather than NaOH
`as used in conventional methods (see paragraph 0077). I note however, that there is no
`experimental data in Kakuta et al. to support the assertion of the Office that Kakuta et al. teaches
`that L-arginine is a stabilizer. (See Example 6.)
`
`6. In fact, there are reports in the literature that arginine can destabilize proteins. For
`example, Rishi et al., Biochem. J. v. 329:137-143 (1998) (attached as Exhibit C) discuss the
`effect of arginine, histidine, and lysine on the stabilization of several different proteins against
`thermal denaturation. Rishi et al. state that arginine appears to bind to denatured molecules and
`destabilized the five different tested proteins when tested using thermal denaturation. (See page
`142, col. 2.)
`
`7. When we were developing a liquid formulation for the recombinant fusion protein
`TNFR:Fc (which contains the extracellular ligand-binding portion of a human p75 tumor
`necrosis factor receptor fused to the F c region of a human IgG 1 ), we looked at a large variety of
`different excipients. One of the ways I studied whether an excipient stabilized the sample was to
`use dynamic light scattering. I measured the light scattering intensity at a 90° angle of a given
`sample (called Is) that had been subjected to time and/ or temperature stress, and compared it to
`the light scattering intensity of a control sample (Ic) at the same 90° degree angle. This
`measurement gave a sensitive indication of whether any aggregation of the sample protein had
`occurred. The ratio was measured as Is/Ic, and a ratio value of one represents a theoretical
`baseline where there was no change in the light scattering intensity (i.e., no aggregation) of the
`test compound or excipient.
`
`--
`
`- - -
`
`---
`
`-
`
`- -- - -
`
`2
`
`Ex. 2015-0014
`
`

`

`DECLARATION OF RICHARD L. REMMELE, JR.
`
`8. The results of one of my time/temperature experiments are graphed in the
`accompanying excerpt from my laboratory notebook, attached as Exhibit D. The dates have been
`redacted to maintain confidentiality. For each time point and experimental condition, I took at
`least 6 samples and calculated the standard deviation. In this particular screening experiment, I
`looked at 5% ascorbic acid, 5.3% mannitol, 10% sucrose, 1% polyvinylpyrrolidone (PVP-K15),
`0.14% polyethylene glycol (PEG, Mw=1000), 0.6% ethanol, 1.2% glycine, 1.5% cysteine, 2.3%
`L-arginine, 0.01% Pluronic F68, and 1.6% Betaine (all proportions are weight/volume, except for
`ethanol).
`
`9. As can be seen in the graph, the results for 2.3% arginine (inverted triangles) stood out
`dramatically. Arginine was profoundly better at stabilizing the protein against aggregation. It
`was unexpected to me that arginine would be so much better than other excipients at stabilizing
`the protein.
`
`I further declare that all statements made herein of my own knowledge are true, that all
`statements made on information and belief are believed to be true, and that these statements were
`made with the knowledge that willful false statements and the like so made are punishable by
`fine or imprisonment, or both (18 USC 1001), and may jeopardize the validity of the application
`or any patent issuing thereon.
`
`~t-'C11aYdLRemmeie)f:
`v '1 t?<J/-1-L ) ,;<, ()() 9
`
`3
`
`Ex. 2015-0015
`
`

`

`DECLARATION OF RICHARD L. REMMELE, JR.
`
`EXHIBIT A
`
`PENDING CLAIMS
`
`57.
`
`A pharmaceutical composition that is a stable aqueous formulation comprising a
`
`polypeptide that is an extracellular ligand-binding portion of a human p75 tumor necrosis factor
`
`receptor fused to the F c region of a human IgG 1 and an aggregation inhibitor, wherein the
`
`aggregation inhibitor is L-arginine at a concentration of from about 10 mM to about 200mM.
`
`58.
`
`The composition of claim 57, further comprising a buffer.
`
`59.
`
`The composition of claim 58, wherein the buffer is selected from the group
`
`consisting of sodium phosphate, histidine, potassium phosphate, sodium or potassium citrate,
`
`maleic acid, ammonium acetate, tris-(hydroxymethyl)-aminomethane (tris), acetate and
`
`diethanolamine.
`
`60.
`
`The composition of claim 59, wherein the L-arginine is at a concentration of from
`
`about 10 mM to about 75 mM.
`
`61.
`
`The composition of claim 60, further comprising a tonicity modifier.
`
`62.
`
`The composition of claim 61, wherein the tonicity modifier is selected from the
`
`group consisting of arginine, cysteine, histidine, glycine, sodium chloride, potassium chloride,
`
`sodium citrate, sucrose, glucose and mannitol.
`
`63.
`
`The composition of claim 62, wherein the tonicity modifier is sodium chloride.
`
`64.
`
`The composition of claim 57, further comprising an excipient.
`
`65.
`
`The composition of claim 63, further comprising an excipient.
`
`66.
`
`The composition of claim 64 wherein the excipient is selected from the group
`
`consisting ofsucrose, lactose~ glycerol~ xylitol,-sorbitof: Manmtof, maltose, mositol, -trehalose,
`
`4
`
`Ex. 2015-0016
`
`

`

`DECLARATION OF RICHARD L. REMMELE, JR.
`
`glucose, bovine serum albumin (BSA), human SA or recombinant HA, dextran, PV A,
`
`hydroxypropyl methylcellulose (HPMC), polyethyleneimine, gelatin, polyvinylpyrrolidone
`
`(PVP), hydroxyethylcellulose (HEC), polyethylene glycol, ethylene glycol, glycerol,
`
`dimethysulfoxide (DMSO), dimethylformamide (DMF), proline, L-serine, sodium glutamic acid,
`
`alanine, glycine, lysine hydrochloride, sarcosine, gamma-aminobutyric acid, Tween-20, Tween-
`
`80, SDS, polysorbate, polyoxyethylene copolymer, potassium phosphate, sodium acetate,
`
`ammonium sulfate, magnesium sulfate, sodium sulfate, trimethylamine N-oxide, betaine, zinc
`
`ions, copper ions, calcium ions, manganese ions, magnesium ions, CHAPS, sucrose monolaurate,
`
`and 2-0-beta-manno glycerate.
`
`67.
`
`The composition of claim 66, wherein the excipient is sucrose.
`
`68.
`
`A stable pharmaceutical composition comprising from about 10 mg/ml to about
`
`1 00 mg/ml etanercept, and further comprising L-arginine, sodium phosphate, sodium chloride
`
`and sucrose.
`
`69.
`
`The composition of claim 68, wherein the L-arginine is at a concentration of from
`
`about 10 mM to about 75 mM.
`
`70.
`
`The composition of claim 68, wherein the sodium phosphate is at a concentration
`
`of from about 5 mM to about 100 mM.
`
`71.
`
`The composition of claim 68, wherein the sodium chloride is at a concentration of
`
`from about 5 mM to about 200 mM.
`
`72.
`
`The composition of claim 68, wherein the sucrose is at a concentration of :from
`
`about 0.5% to about 1.5%.
`
`73.
`
`The composition of claim 68, wherein the pH of the composition is from about
`
`5.5 to about 7.8.
`
`5
`
`Ex. 2015-0017
`
`

`

`DECLARATION OF RICHARD L. REMMELE, JR.
`
`74.
`
`The composition of claim 68, comprising from 25 to 50 mg/ml etanercept,