I hereby certify that this paper (along wi1h any paper referred to as being attached
`or enclosed) is being transmitted via the Office electronic filing system in
`accordance with 37 CFR § 1.6(a)(4).
`
`Dated: December 3, 2013
`
`Signature:
`
`/Sharon M. Sintich/
`(Sharon M. Sin1ich)
`
`Docket No.: 32053/46964
`(PATENT)
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In re Patent Application of:
`Dingjiang Liu et al.
`
`Application No.: 13/521,999
`
`Confirmation No.: 9453
`
`Filed: July 12, 2012
`
`For: ANTIBODY FORMULATION AND
`THERAPEUTIC REGIMENS
`
`A1i Unit: 1646
`
`Examiner: D. Jiang
`
`AMENDMENT AND REQUEST FOR RECONSIDERATION
`
`MS Amendment
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`Dear Madam:
`
`This is a response to the Office Action dated September 3, 2013 in which
`
`pending claims 1-3 and 5-10 were rejected under 35 U.S.C. §§ 103(a) and 112, second
`
`paragraph. This response is timely filed.
`
`Please amend the application as follows:
`
`Amendments to the Claims are reflected in the listing which begins on page
`
`2 of this paper.
`
`Remarks begin on page 5 of this paper.
`
`1
`
`Ex. 2007-0001
`
`

`
`Application No.: 13/521,999
`
`Docket No.: 32053/46964
`
`AMENDMENTS TO THE CLAIMS
`
`This listing of claims will replace all prior versions, and listing of claims in the
`
`application:
`
`Listing of Claims:
`
`1.
`
`(currently amended) A pharmaceutical formulation, comprising an
`
`aqueous solution of a glutamic acid buffer and an antibody or a fragment thereof comprising
`
`a heavy chain CDRl comprising SEQ ID N0:5, a heavy chain CDR2 comprising SEQ ID
`
`N0:7, a heavy chain CDR3 comprising SEQ ID N0:8, a light chain CDRl comprising SEQ
`
`ID N0:9, a light chain CDR2 comprising SEQ ID NO: 10, and a light chain CDR3
`
`comprising SEQ ID NO: 11, wherein said antibody, or fragment thereof, specifically binds
`
`human IL-17 receptor A, and wherein:
`
`a)
`
`said formulation gl1:1atmic acid buffer comprises a glutamic acid
`
`concentration of 10 + 0.2 mM 5.30 m-M: 1 0.2 ffi~4;
`
`b)
`
`c)
`
`said formulation gluatFH:ic acid buffer comprises a pH of 4.5-5.2 ± 0.2;
`
`said formulation fmther comprises 3 + 0.2% 2-4% proline (w/v) and
`
`0.01 ± 0.002% 0.005 0.02% (w/v) polysorbate 20; aBEl
`
`d)
`
`said antibody is at a concentration of about 140 ± 5% 100 te 150
`
`mg/ml; and
`
`e)
`
`said fonnulation has a viscosity of 5 to 7 cP at 25 degrees C.
`
`2.
`
`(original) The pharmaceutical formulation of claim 1, wherein the
`
`antibody or fragment thereof comprises a heavy chain variable domain sequence comprising
`
`SEQ ID N0:3 and a light chain vmiable domain sequence comp1ising SEQ ID N0:4.
`
`3.
`
`(original) The pharmaceutical formulation of claim 1, wherein the
`
`antibody comprises a heavy chain sequence comprising SEQ ID N0:1 and a light chain
`
`sequence comprising SEQ ID N0:2, or alternatively, a heavy chain sequence comprising
`
`SEQ ID N0:12 and the light chain sequence comprising SEQ ID N0:2.
`
`4.
`
`(withdrawn) The pharmaceutical formulation of claim 1, further
`
`comp1ising an osmolarity of 275 to 325 osm.
`
`2
`
`Ex. 2007-0002
`
`

`
`Application No.: 13/521,999
`
`Docket No.: 32053/46964
`
`Claims 5 - 8
`
`(canceled)
`
`(currently amended) A pharmaceutical container, comprising a vessel
`9.
`and the pharmaceutical formulation of any of claims 1 to [[8]] :L wherein the vessel is a vial,
`
`bottle, pre-filled syringe, or pre-filled autoinjector syringe.
`
`10.
`
`(original) A kit, comprising one or more pharmaceutical containers
`
`according to claim 9 and instructions regarding the use thereof.
`
`11.
`
`(withdrawn) A method of treating psoriasis in a human patient in need
`
`thereof, comprising administering to the patient a single or divided 70 to 1,000 mg dose of an
`
`antibody, wherein said antibody is selected from the group consisting of:
`
`a)
`
`an antibody comprising a heavy chain CDRl comprising SEQ ID
`
`N0:5, a heavy chain CDR2 comprising SEQ ID N0:7, a heavy chain CDR3 comprising SEQ
`
`ID N0:8, a light chain CDRl comprising SEQ ID N0:9, a light chain CDR2 comprising SEQ
`
`ID NO: 10, and a light chain CDR3 comprising SEQ ID NO: 11, wherein said antibody, or
`
`fragment thereof, specifically binds human IL-17 receptor A;
`
`b)
`
`an antibody comprising a heavy chain variable domain sequence
`
`comprising SEQ ID N0:3 and a light chain variable domain sequence comprising SEQ ID
`
`N0:4, wherein said antibody, or fragment thereof, specifically binds human IL-17 receptor
`
`A; and
`
`c)
`
`an antibody comprising a heavy chain sequence comprising SEQ ID
`
`NO: 1 and a light chain sequence comprising SEQ ID N0:2, or alternatively, a heavy chain
`
`sequence comprising SEQ ID NO: 12 and the light chain sequence comprising SEQ ID N0:2.
`
`12.
`
`(withdrawn) The method of claim 11, wherein said patient is
`
`administered a single or divided 70 to 280 mg dose of said antibody administered at time "0"
`
`(the first administration), at one week post time "0" (week one), and then administered every
`
`two to four weeks following the week one administration.
`
`13.
`
`(withdrawn) The method of claim 12, wherein a single or divided dose
`
`of 140 mg of said antibody is administered at time "0" (the first administration), at one week
`
`post time "0" (week one), and then administered every two weeks to patients weighing less
`
`than or approximately equal to 100 kg, and wherein a single or divided dose of 280 mg of
`3
`
`Ex. 2007-0003
`
`

`
`Application No.: 13/521,999
`
`Docket No.: 32053/46964
`
`said antibody is administered at time "0" (the first administration), at one week post time "0"
`
`(week one), and then administered every two weeks to patients weighing greater than 100 kg.
`
`14.
`
`(withdrawn) The method of any of claims 11 to 13, wherein the
`
`psoriasis is selected from the group consisting of:
`
`a)
`
`b)
`
`c)
`
`plaque psoriasis;
`
`moderate to severe plaque psoriasis;
`
`chronic moderate to severe plaque psoriasis and said patients are
`
`candidates for systemic therapy or phototherapy; and
`
`d)
`
`chronic moderate to severe plaque psoriasis and wherein said patients
`
`have failed to respond to, have a contraindication to, or are intolerant to other systemic
`
`therapies including cyclosporin, methotrexate, and psoralen plus ultraviolet-A phototherapy.
`
`15.
`
`(withdrawn) The method of any of claims 11 to 14, wherein said
`
`antibody is in a pharmaceutical formulation comprising about 140 mg/mL of said antibody,
`
`formulated with 10 ± 0.2 mM glutamic acid, 3 ± 0.2% (w/v) L-proline, 0.01 ± 0.002% (w/v)
`
`polysorbate 20, pH 4.8 ± 0.2.
`
`16.
`
`(withdrawn) The method of claim 15, wherein the pharmaceutical
`
`formulation is administered subcutaneously, intradetmally, intramusclularly, and/or
`
`intravenous! y.
`
`4
`
`Ex. 2007-0004
`
`

`
`Application No.: 13/521,999
`
`Docket No.: 32053/46964
`
`REMARKS
`
`I.
`
`The Rejection Under 35 U.S.C. § 112, Second Paragraph Should be Withdrawn
`
`Claims 1-3 and 5-10 were rejected under 35 U.S.C. § 112, second paragraph for
`
`allegedly being indefinite for failing to particularly point out and distinctly claim the subject
`
`matter of the invention. Applicants traverse this rejection.
`
`The Examiner stated that the phrase "wherein the antibody or fragment thereof' in
`
`claim 1 lacks proper antecedent basis. In response, claim 1 is amended to recite that the
`
`formulation comprises "an aqueous solution of a glutamic acid buffer and an antibody or a
`
`fragment thereof comprising ... "
`
`In addition, the Examiner stated that the claimed "pharmaceutical container,
`
`comprising a vessel and the pharmaceutical formulation" in claim 9 is indefinite because a
`
`container usually contains a vessel and pharmaceutical composition rather than comp1ise a
`
`vessel and pharmaceutical composition. Applicants traverse this rejection. According to
`
`MPEP § 2111.03, the transitional term "comprising" is synonymous with the term
`
`"containing." Comprising is a term of art used in claim language which means the named
`
`elements are essential, but other elements may be added and still form a construct within the
`
`scope of the claims. Moleculcon Research Corp. v. CBS, Inc. 793 F.2d 1261, 229 USPQ 805
`
`(Fed. Circ. 1986).
`
`In view of the foregoing amendment and remarks, the claims are definite and clear.
`
`Applicants request that the rejection under 35 U.S.C. § 112, second paragraph be withdrawn.
`
`II.
`
`The Rejection Under 35 U.S.C. 103(a) Should be Withdrawn
`
`Claims 1-3 and 5-10 were rejected under 35 U.S.C. § 103(a) as allegedly being
`
`obvious in view of Tocker et al. (US 2008/0221307) and Jacob et al. (US 2008/0213282).
`
`Applicants traverse this rejection.
`
`A.
`
`Claimed Invention
`
`The claimed pharmaceutical formulations comprise an aqueous solution of a glumatic
`
`acid buffer and a specific antibody at a concentration of about 140 ± 5% mg/ml, wherein the
`
`formulation has particularly defined characteristics such as glutamic acid concentration,
`
`proline concentration, polysorbate 20 concentration, pH and viscosity. The claimed
`
`pharmaceutical formulations are tailored and optimized for a specific antibody that achieved
`5
`
`Ex. 2007-0005
`
`

`
`Application No.: 13/521,999
`
`Docket No.: 32053/46964
`
`three critical, but countervailing objectives: high concentration, low viscosity, and stability.
`
`It is well established in the art that formulating high concentration antibody solutions having
`
`low viscosity that stabilize the antibody is highly desirable, but very difficult to achieve and
`
`certainly not predictable. By achieving this, critical downstream advantages are also
`
`achieved, such as enhanced manufacturability, enhanced adaptability to standard devices,
`
`such as autoinjectors, lower volume administration resulting in less injection site discomfort
`
`to patients (see page 4, line 34 through page 5, line 13 of the specification).
`
`B.
`
`No Prima Facie Case of Obviousness
`
`When rejecting claims under 35 U.S.C. §103, the examiner bears the initial burden of
`
`factually supporting any prima facie conclusion of obviousness. To establish a prima facie
`
`case of obviousness, the examiner must determine that the invention as a whole would have
`
`been obvious to a person of ordinary skill in the art at the time of filing. To support the
`
`conclusion that the claimed invention is obvious, either the cited references must expressly or
`
`impliedly suggest the claimed invention or the examiner must present a convincing line of
`
`reasoning as to why the artisan would have found the claimed invention to have been obvious
`
`in light of the teachings of the references. Ex parte Clapp, 227 USPQ 972, 973 (Bd. Pat. App.
`
`& Inter. 1985). In order for the combined teachings cited by the Examiner to establish a
`
`prima facie case of obviousness, the combination must yield a predictable result. When the
`
`Examiner combines multiple references in order to establish a prima facie case of
`
`obviousness, one of skill in the art must recognize that the results of the combination would
`
`be predictable. KSR Intl' Co. v. Teleflex Inc. 127 S. Ct. 1727, 1740, 82 US USPQ 2d 1385,
`
`1395 (2007).
`
`The claimed formulations complise a high concentration of antibody while having
`
`low viscosity and stability. One of skill in the art would not expect a formulation having a
`
`high concentration of antibody to have the resulting characteristics in view of the
`
`combination of Tacker and Jacobs. While Tocker teaches formulations comprising the
`
`antibody recited in the claims, as acknowledged by the Examiner, it does not teach the
`
`formulation having the claim-recited characteristics. Jacobs provides glutamate/proline
`
`formulations for antibodies amongst a wide range of variables. It was not obvioius to try the
`
`multiple valiables taught in Jacobs with the expectation that the resulting pharmaceutical
`
`6
`
`Ex. 2007-0006
`
`

`
`Application No.: 13/521,999
`
`Docket No.: 32053/46964
`
`formulation would comprise a high concentration of antibody with low viscosity and
`
`stability.
`
`The Examiner pointed to sections in Jacobs that allegedly teach the characteristics of
`
`the claimed pharmaceutical formulations, but these assertions are biased by hindsight.
`
`Jacobs discloses an incalculable number of possible formulations, such as glutamic acid or
`
`acetic acid or aspartic acid buffers that can optionally include other salts, such as sodium,
`
`potassium, ammonium, calcium or magnesium at concentrations anywhere between 1 and
`
`150 mM; pH ranges from about 4 to about 6 with an unspecified amount of proline or from
`
`about 1-30%. The formulations may also include any of an exhaustive list of excipients
`
`[0048 and 0095] at concentrations ranging from 1 to over 75% [0094], various sugar alcohols
`
`[0049], reducing sugars [0050], tonicity agents and/or stabilizers [0052], anti-oxidants
`
`[0053], metal ions [0054], preservatives [0055], surfactants [0056 and 0099] at concentration
`
`ranges less than 1% (w/v) [0098], non-ionic surfactants [0057], ionic surfactants [0058], and
`
`antibodies/peptibodies/fusion proteins/polypeptides at concentrations from 1 to about 200
`
`mg/ml [0142]. Therefore, the vast majmity of what Jacobs discloses teaches away from the
`
`invention.
`
`Thus, the characteristics of the claimed formulations are not a predictable result
`
`required to establish a prima facie of obviousness. One of skill in the art would not have a
`
`reasonable expectation of success selecting from the wide range of variables in Jacobs to
`
`result in a formulation having a high concentration of the specific claim-recited antibody, low
`
`viscosity and stability.
`
`Obviousness cannot be assessed in light of only the prior art cited by the Examiner,
`
`but rather, from the whole of the relevant art. There is a massive amount of prior art
`
`suggesting alternative protein formulations. All of these advocate different formulations than
`
`those claimed, and therefore, teach away from the present invention. At the time the
`
`invention was made, one of skill in the art would be faced with, for all practical purposes, an
`
`endless number of possible formulations given all the permutations of the various
`
`components, concentrations of components, and physical parameters (monoclonal antibody
`
`sequence, pH, viscosity, etc.). The number of possible options are not finite or known, as
`
`required by law, and therefore it is not "obvious to try" and invariably and predictably arrive
`
`at the claimed invention (Abbott Labs v. Sandoz, 544 F.3d 1341, 1351 (Fed. Circ. 2008). In
`
`7
`
`Ex. 2007-0007
`
`

`
`Application No.: 13/521,999
`
`Docket No.: 32053/46964
`
`order to anive at the claimed formulation from the combination of Tocker and Jacobs, one of
`
`skill in the art must vary many or all of the parameters provided in the art to arrive at the
`
`claimed pharmaceutical formulation which is quite different than known fact patterns that
`
`were determined to be obvious to try (see, e.g. Perfect Web Techs v Info USA 587 F3d
`
`1324, 1331 (Fed. Circ. 2009).
`
`C.
`
`Unexpected Results
`
`To rebut a prima facie case of obviousness, Applicants may provide evidence of
`
`secondary considerations such as unexpected results. In particular, the data in Example 1
`
`demonstrates that formulations comprising a glutamate acid buffer, polysorbate 20, proline
`
`and a high concentration of antibody had a lower viscosity (see Table 1.1, formulations
`
`E48PT and E52PT at pp. 40 and 41) than the other formulations tested. Further, Tables 1.4
`
`and 1.5 show that these formulations were stable over 3 months at 4°C or at 25°C,
`
`respectively, in a pre-filled syringe (seep. 42). It was unexpected that the claimed
`
`formulations comprise a high concentration of antibody, are stable and have a surprisingly
`
`low viscosity. As stated above, it is well known that formulating high concentration antibody
`
`solutions having low viscosity that stabilize the antibody is highly desirable, but very difficult
`
`to achieve and certainly not predictable.
`
`At page 5 of the Office Action, the Examiner states "[ w ]ith respect to the limitation of
`
`viscosity in claim 5, it would be the inherent property of the formulation as it is dependent
`
`upon the components of the formulation (excipientldiluents)." This is not correct. It was
`
`well established in the art that the antibody is the main source of viscosity. As evidence,
`
`Kamerzell et al. (1. Phys. Chern. 2009, 113, 6109-6118) is provided as Exhibit A), which
`
`states at page 6109 lower left column that "It has been shown that increasing immunoglobulin
`
`(IgG) concentration increases self-association of these molecules resulting in increased
`
`nonideal solution properties and significantly affects the viscosity and rheological behavior."
`
`It was also well known in the art that formulating high concentration antibody solutions
`
`having acceptable viscosity was highly unpredictable and could only be achieved empirically.
`
`As evidence of the high unpredictability in this art and especially as it relates to viscosity,
`
`Kamerzell describes analyzing two monoclonal antibodies with sequences that only differed
`
`in the CDRs and yet had " ... widely differing solution behavior." (see page 6113, lower right
`
`column to page 6115, upper left column).
`
`8
`
`Ex. 2007-0008
`
`

`
`Application No.: 13/521,999
`
`Docket No.: 32053/46964
`
`Therefore, a stable, high-concentration, formulation with low viscosity is a delicate
`
`interplay between the components of the formulation and the sequence/structure of the
`
`particular antibody. Whether a particular formulation will achieve these results cannot be
`
`predicted a priori and is only the result of inventive ingenuity. Neither Tacker nor Jacobs,
`
`alone or in combination, teach or suggest the particular formulation encompassing the
`
`specific antibody having the claimed attributes. One of skill of art at the time the invention
`
`was made would have absolutely no clue as to whether any specific formulation for the
`
`particular antibody of the claims would achieve the surprisingly successful invention.
`
`Consequently, there is no reasonable expectation of success due to this unpredictability.
`
`D.
`
`Conclusion
`
`In view of the foregoing amendment and remarks, claims 1-3 and 5-10 are not
`
`obvious in view of Tacker and Jacobs. Applicants request that the rejection under 35 U.S.C.
`
`§ 103 be withdrawn.
`
`CONCLUSION
`
`Applicants believe pending claims 1-3 and 5-10 are in condition for allowance and
`
`early notice thereof is requested.
`
`Dated: December 3, 2013
`
`Respectfully submitted,
`
`By /Sharon M. Sintich/
`Sharon M. Sintich
`Registration No.: 48,484
`MARSHALL, GERSTEIN & BORUN LLP
`233 S. Wacker Drive
`6300 Willis Tower
`Chicago, Illinois 60606-6357
`(312) 474-6300
`Attorney for Applicant
`
`9
`
`Ex. 2007-0009