8232693
`
`UNITED STATES DEPARTMENT OF COMMERCE
`
`United Stntcs Pntcnt nnd Trndcmnrk Office
`
`April 01, 2022
`
`THIS IS TO CERTIFY THAT ANNEXED IS A TRUE COPY FROM THE
`RECORDS OF THIS OFFICE OF THE FILE WRAPPER AND CONTENTS
`OF:
`
`APPLICATION NUMBER: 13/938,923
`FILING DATE: July 10, 2013
`PATENT NUMBER: 8911993
`ISSUE DATE: December 16, 2014
`
`Certified by
`
`Under Secretary of Commerce
`for lntelJectual Property
`and Director of the United States
`Patent and Trademark Office
`
`Miltenyi Ex. 1041 Page 1
`
`Miltenyi Ex. 1041 Page 1
`
`

`

`U.S. Application No. 13/938,923
`Amendment in response to final Office Action dated March 28, 2014
`
`ELECTRONICALLY FILED
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In re Application of:
`Carl H. June et al.
`
`Application No.: 13/938,923
`
`Filed: July l 0, 2013
`
`Title: Compositions for Treatment of Cancer
`
`Confirmation No.: 9898
`
`Group A rt Unit: 1633
`
`Examiner: Burkhart, Michael D.
`
`A ttorney Docket No.
`046483-6001 US2 (00169)
`
`AMENDMENT
`
`This Amendment responds to the final Office Action dated March 28, 2014, sent
`in connection with the above-identified application.
`
`A Petition for a three month extension of time and associated fee is included
`herewith which extends the time for the response to the Office Action through and to September
`28, 2014.
`
`A Request for Continued Examination (RCE) and associated fee is being filed
`simultaneously herewith.
`
`A Certification and Request for Prioritized Examination under 37 C.F.R. 1.102( e)
`(Track I) and associated fee is being filed simultaneously herewith.
`
`A Supplemental Information Disclosure Statement and Form 1449 is being fi led
`simultaneously herewith.
`
`A Request for Examiner Interview in person at the USPTO with the Examiner and
`his Supervising Examiner, is being filed simultaneously herewith.
`
`A Declaration of Dr. Carl June is being filed simultaneously herewith.
`
`Miltenyi Ex. 1041 Page 2
`
`

`

`U.S. Application No. 13/938,923
`Amendment in response to final Office Action dated March 28, 2014
`
`Please charge the any underpayment of fee, or credit any overpayment, to Deposit
`Account No. 50-4364.
`
`Amendments to the claims begin on page 3 of this paper.
`
`Remarks begin on page 6 on this paper.
`
`- 2 -
`
`Miltenyi Ex. 1041 Page 3
`
`

`

`U.S. Application No. 13/938,923
`Amendment in response to final Office Action dated March 28, 2014
`
`In the Claims:
`The listing of the claims will replace all prior versions, and listings, of claims in
`the application.
`
`1 to 89. ( canceled)
`
`90. (currently amended) A pharmaceutical composition comprising an anti-tumor effective
`amount of a population of modified a\:itologous human T cells, wherein the T cells comprise a
`nucleic acid sequence that encodes a chimeric antigen receptor (CAR), wherein the CAR
`comprises a CD 19 antigen binding domain comprising the amino acid sequence of SEO ID NO:
`20, a CD8a hinge domain, a CD8a transmembrane domain, a 4-1 BB costimulatory signaling
`region, and a CD3 zeta signaling domain comprising the amino acid sequence of SEO ID N0:24;
`,¥herein the anti tumor effective amount of T cells is l 04 te--1-09 cells per kg body weight of a
`human in need of sueh cells, wherein the T cells are T cells of a human having a cancer.
`
`91. ( canceled)
`
`92. (currently amended) The composition of claim 90, wherein the anti-tumor effective amount
`of T cells is 104 .W~ to 109 -l-06 cells per kg body weight of the£! human in need of such cells.
`
`93 to 95. (canceled)
`
`97. (previously presented) The composition of claim 90, wherein the CD8a transmembrane
`domain comprises the amino acid sequence of SEQ ID NO: 22.
`
`98. (previously presented) The composition of claim 90, wherein the CD8a hinge domain
`comprises the amino acid sequence of SEQ ID NO: 21.
`
`99. (previously presented) The composition of claim 90, wherein the 4-lBB costimulatory
`signaling region comprises the amino acid sequence of SEQ ID NO: 23.
`
`- 3 -
`
`Miltenyi Ex. 1041 Page 4
`
`

`

`U.S. Application No. 13/938,923
`Amendment in response to final Office Action dated March 28, 2014
`
`100. (canceled)
`
`IO 1. ( currently amended) The composition of claim [[96]] 90, wherein the sew CD 19 antigen
`binding domain is encoded by a nucleic acid sequence comprising SEQ ID NO: 14.
`
`102. (previously presented) The composition of claim 97, wherein the CD8a transmembrane
`
`domain is encoded by a nucleic acid sequence comprising SEQ ID NO: 16.
`
`103. (previously presented) The composition of claim 98, wherein the CD8a hinge domain is
`
`encoded by a nucleic acid sequence comprising SEQ ID NO: 15.
`
`104. (previously presented) The composition of claim 99, wherein the 4-lBB costimulatory
`
`signaling region is encoded by a nucleic acid sequence comprising SEQ ID NO: 17.
`
`105. (currently amended) The composition of claim [[100]] 90, wherein the CD3 zeta signaling
`
`domain is encoded by a nucleic acid sequence comprising SEQ ID NO: 18.
`
`106. (new) The composition of claim 97, wherein the 4-1 BB costimulatory signaling region
`
`comprises the amino acid sequence of SEQ ID NO:23.
`
`107. (new) The composition of claim 106, wherein the 4- 1 BB costimulatory signaling region of
`
`the CAR is encoded by a nucleic acid sequence comprising SEQ ID NO: 17.
`
`108. (new) The composition of claim 98, wherein the 4-1 BB costimulatory signaling region
`
`comprises the amino acid sequence of SEQ ID NO:23.
`
`109. (new) The composition of claim 108, wherein the 4-1 BB costimulatory signaling region is
`
`encoded by a nucleic acid sequence comprising SEQ ID NO: 1 7.
`
`110. (new) A pharmaceutical composition comprising an anti-tumor effective amount of a
`
`population of human T cells, wherein the T cells comprise a nucleic acid sequence that encodes a
`
`- 4 -
`
`Miltenyi Ex. 1041 Page 5
`
`

`

`U.S. Application No. 13/938,923
`Amendment in response to final Office Action dated March 28, 2014
`
`chimeric antigen receptor (CAR), wherein the CAR comprises a CD19 antigen binding domain
`comprising the amino acid sequence of SEQ ID NO:20, a CD8a. hinge domain comprising the
`amino acid sequence of SEQ ID NO:21, a CD8a. transmembrane domain comprising the amino
`acid sequence of SEQ ID NO:22, a 4-lBB costimulatory signaling region comprising the amino
`acid sequence of SEQ ID NO:23, and a CD3 zeta signaling domain comprising the amino acid
`sequence of SEQ ID NO:24, wherein the T cells are T cells of a human having a cancer.
`
`111. (new) The composition of claim 110, wherein the CD 19 antigen binding domain of the
`CAR is encoded by a nucleic acid sequence comprising SEQ ID NO: 14, the CD8a. hinge domain
`of the CAR is encoded by a nucleic acid sequence comprising SEQ ID NO: 15, the CD8a.
`transmembrane domain of the CAR is encoded by a nucleic acid sequence comprising SEQ ID
`NO: 16, the 4-1 BB costimulatory signaling region of the CAR is encoded by a nucleic acid
`sequence comprising SEQ ID NO: 17, and the CD3 zeta signaling domain of the CAR is encoded
`by a nucleic acid sequence comprising SEQ ID NO: 18.
`
`112. (new) The composition of claim 110, wherein the anti-tumor effective amount of T cells is
`104 to 109 cells per kg body weight of a human in need of such cells.
`
`113. (new) The composition of claim 110, wherein the anti-tumor effective amount ofT cells is
`105 to 106 cells per kg body weight of a human in need of such cells.
`
`114. (new) The composition of claim 90, wherein the anti-tumor effective amount of T cells is
`l 05 to 106 cells per kg body weight of a human in need of such cells.
`
`115. (new) The composition of claim 97, wherein the CD8a hinge domain comprises the amino
`acid sequence of SEQ ID NO: 21.
`
`116. (new) The composition of claim 115, wherein the CD8a. hinge domain is encoded by a
`nucleic acid sequence comprising SEQ ID NO: 15.
`
`- 5 -
`
`Miltenyi Ex. 1041 Page 6
`
`

`

`U.S. Application No. 13/938,923
`Amendment in response to final Office Action dated March 28, 2014
`
`REMARKS
`The present application is a continuation of and claims priority to U.S. Patent
`Application No. 13/992,622, filed June 7, 2013, which is a national phase application of
`International Application No. PCT/US201 l/064191, filed December 9, 2011, which claims
`priority to U.S. Provisional Patent Application No. 61/421,470, filed on December 9, 2010 and
`U.S. Provisional Patent Application No. 61/502,649, filed on June 29, 201 1.
`In a Preliminary Amendment filed July 10, 2013, claims 1-89 were canceled and
`new claims 90-105 were added. In the Amendment filed on December 19, 2013, claims 90 and
`92 were amended and claim 91 was canceled. In the present Amendment, claims 90, 92, 101 and
`105 are amended, claims 93, 94, 95, 96 and 100 are canceled, and claims 106 to 116 are newly
`added.
`
`Therefore, claims 90, 92, 97-99, and 101-116 are currently under consideration.
`Applicants hereby incorporate by reference their arguments made in the
`Amendment filed on December 20, 2013 as if included herein in their entirety.
`
`Amendment to the Claims
`Claim 90 has been amended herein to recite that the CDl 9 antigen binding
`domain comprises the amino acid sequence of SEQ ID NO:20, support for which amendment is
`found in canceled claim 96 and in paragraph (0136] of US Publication No. 2013/0288368 Al ,
`the instant published application.
`Claim 90 has also been amended to recite that the CD3 zeta signaling domain
`comprises the amino acid sequence of SEQ ID NO:24, support for which amendment is found in
`canceled claim 100 and in paragraph [0152] of US Publication No. 2013/0288368 A l.
`Claim 90 has been amended to delete the term "autologous" and to recite
`"wherein the T cells are T cells of a human having cancer." Support for this amendment is found
`throughout the Examples where the T cells that are modified and administered to a patient are T
`cells from a human having cancer.
`Claim 92 has been amended to recite "wherein the anti-tumor effective amount of
`T cells is 104 to 109 cells per kg body weight of the a human in need of such cells." Support for
`
`- 6 -
`
`Miltenyi Ex. 1041 Page 7
`
`

`

`U.S. Application No. 13/938,923
`Amendment in response to final Office Action dated March 28, 2014
`
`this amendment is found in previously amended claim 90 and in paragraph [0224] of US
`Publication No. 2013/0288368 A I.
`Claim 101 has been amended to depend from claim 90 and to specify that the
`CD19 antigen binding domain is encoded by a nucleic acid sequence comprising SEQ ID NO:14.
`Support for this amendment is found in originally filed claim 101 and in paragraph [0136] of US
`Publication No. 2013/0288368 Al.
`Claim 105 bas been amended to depend from claim 90.
`New claims 106-112, and 1 16 and 117 recite components of the pharmaceutical
`composition of the invention identified by SEQ ID NOs. Referring to US Publication No.
`2013/0288368 Al: Support for SEQ ID NO:15 is found in paragraph (0141]; support for SEQ ID
`NO:23 is found in paragraph (0152]; support for SEQ ID NO:17 is found in paragraph (0151];
`support for SEQ ID NO:14 is found in paragraph [0136]; support for SEQ ID NO:1"6 is found in
`paragraph [0140]; and, support for SEQ ID NO:18 is found in paragraph (0151].
`New claims 113, 114 and 115 recite anti-tumor effective amounts ofT cells where
`support is found in paragraph (0224] of US Publication No. 2013/0288368 Al.
`No new matter has been added by way of Applicants' amendment or addition to
`
`the claims.
`
`Prior Art Reiections
`Applicants note that previously pending claims 96 and 101, each of which depend
`from claim 90 and recite the amino acid and nucleic acid sequences of the CD 19 antigen binding
`domain, respectively, have not been rejected over the prior art ofrecord. Claim 90 has been
`amended herein to incorporate the subject matter of previously pending claim 96.
`
`Rejection of Claims 90 and 92-95 under 35 U.S.C. § 102(b)
`Claims 90 and 92-95 stand rejected under 35 U.S.C. § 102(b) as allegedly being
`anticipated by Milone et al. (Mo!. Ther., 17(8), p. 1453-64, 2009; hereinafter "Milone"). In the
`Examiner's view, Milone teaches autologous T cells because according to the Examiner, "the
`human T cells used by Milone are autologous with respect to the individual they were prepared
`from."
`
`- 7 -
`
`Miltenyi Ex. 1041 Page 8
`
`

`

`U.S. Application No. 13/938,923
`Amendment in response to final Office Action dated March 28, 2014
`
`As a first matter, claims 93-95 are canceled herein. The rejection is therefore
`addressed herein with respect to claims 90 and 92.
`Claims 90 and 92 are not anticipated by Milone. Applicants respectfully disagree
`with the Examiner's read of the term "autologous." This term is clearly defined in the
`specification at paragraph [0075] in US Publication No. 2013/0288368 Al, as "any material
`derived from the same individual to which it is later to be re-introduced into that individual."
`The term "autologous" relates to not just to the cell donor, but also the recipient of the cells.
`Applicants' definition of autologous embodies the common use of the term in the biological arts.
`Further, the statement by the Examiner that the "T cells used by Milone are
`autologous with respect to the individual they were prepared from" indicates that the Examiner
`equates Milone's introduction of human T cells into a mouse to somehow constitute an
`"autologous" T cell transfer. This assumption by the Examiner flies in the face of years of
`scientific research and discovery on the characterization of cells that are defined in the art as
`being autologous, homologous, or heterologous. If the Examiner's reasoning were to prevail, all
`cells from a donor would be viewed as being autologous cells irrespective of the host into which
`they might be introduced. There would be no need to characterize cells as being alternatively
`homologous or heterologous, for example. Applicants submit that the fields of transplantation
`biology, cancer therapy, to name a few, would have very different outcomes if the Examiner's
`notion of autologous were correct. The meaning of autologous is clear. The Examiner's
`interpretation is improper.
`Notwithstanding Applicants' position on the term autologous, in an effort to
`expedite prosecution of the instant claims, Applicants have amended claim 90 and dependent
`claims therefrom, to delete the term autologous and recite instead that "the T cells are T cells of a
`human having a cancer." It is clear from the Examples in the instant specification that the
`claimed T cells are cells of a human having cancer.
`It is also clear that the T cells taught in Milone are not T cells of a human having
`cancer. In the Supplementary Materials and Methods section of Milone, on the first page under
`the heading "Primary cells and cell lines," in the first line, it is stated that "Peripheral blood
`mononuclear cells (PBMC) were obtained from healthy donors by apheresis." [Emphasis added]
`T cells from humans having cancer have a different phenotype than T cells from a healthy
`human. See for example, Ochoa et al. (Immune defects in T cells from cancer patients, parallels
`
`- 8 -
`
`Miltenyi Ex. 1041 Page 9
`
`

`

`U.S. Application No. 13/938,923
`Amendment in response to final Office Action dated March 28, 2014
`
`in infectious disease, from: Cancer Immunotherapy at the Crossroads: how tumors evade
`immunity and what can be done (current clinical oncology), edited by James H. Finke, Ronald
`M. Bukowski, 2004 edition), included herewith in the Supplemental Information Disclosure
`Statement. The T cells of Milone are not Applicants' claimed T cells.
`Further, Milone does not disclose, inter alia, a CD3zeta signaling domain
`comprising the amino acid sequence of SEQ ID NO:24.
`It is well-settled law that "[a] claim is anticipated only if each and every element
`as set forth in the claim is found, either expressly or inherently described, in a single prior art
`reference." MPEP § 2131 (quoting Verdegaal Bros. v. Union Oil Co. of Calif., 814 F.2d 628,
`631 (Fed. Cir. 1987)). "The identical invention must be shown in as complete detail as is
`contained in the ... claim." Id. (quoting Richardson v. Suzuki Motor Co., 868 F.2d 1226, 1236
`(Fed. Cir. 1989) (emphasis added)). Therefore, Milone must describe each and every element of
`a claim in order to be an anticipating reference under 35 U.S.C. § 102(b). Milone does not
`satisfy this requirement.
`Milone cannot anticipate the present claims and Applicants respectfully request
`reconsideration and withdrawal of the rejection of claims 90 and 92 under 35 U.S.C. § 102(b) as
`being anticipated by Milone.
`
`Reiection of Claims 97-99 and 102-104 under 35 U.S.C. § 103(a)
`The Examiner has maintained the rejection of claims 97-99 and 102-104 under 35
`U.S.C. § 103(a) as allegedly being obvious over Milone as applied to claims 90-95, in view of
`Rosenberg et al. (U.S. Patent No. 8,465,743; hereinafter "Rosenberg").
`Addressing the Examiner's statements regarding Applicants' arguments in the
`Amendment dated December 20, 2013:
`
`1) The Examiner notes that Applicants' statement that Milone does not teach
`autologous human T cells is false. With all due respect, for the reasons given above, the
`Examiner is mistaken. Under any definition of the term "autologous" and especially Applicants'
`definition of this term in paragraph [0075] of US Publication No. 2013/0288368 Al, Milone
`does not teach autologous T cells. Nonetheless, claim 90 has been amended herein to delete the
`
`- 9 -
`
`Miltenyi Ex. 1041 Page 10
`
`

`

`U.S. Application No. 13/938,923
`Amendment in response to final Office Action dated March 28, 2014
`
`tenn "autologous" and recite that "the T cells are T cells of a human having a cancer." Milone
`nowhere teaches such T cells.
`
`2) The Examiner argues that Milone provides a credible model of leukemia.
`Applicants stand by their arguments made in the Amendment dated December 20, 2014.
`
`3) With regard to Applicants' arguments that Rosenberg does not cure the
`deficiencies in Milone, the Examiner asserts that "one cannot show nonobviousness by attacking
`references individually". Applicants do not understand the Examiner's reasoning. On page 10
`of the Amendment dated December 20, 2013, Applicants clearly address the Examiner's
`rejection by discussing the combination of Milone and Rosenberg- see first, second and third
`full paragraphs of page 10 of the Amendment.
`The Examiner concedes that Milone does not specifically teach the use of SEQ ID
`NOS: 22 or 21 as the amino acid sequence of the CD8 alpha hinge and transmembrane domains,
`and does not teach SEQ ID NO: 23 as the amino acid sequence of the 4-lBB region. The
`Examiner states that Rosenberg teaches these sequences, and their corresponding nucleic acid
`sequences (SEQ ID NOS: 16, 15 and 17) within a CAR. The Examiner further opines that
`Applicants' claimed T cells are essentially disclosed by Milone with the exception of the specific
`sequences and therefore the combination of Milone in view of Rosenberg renders claims 97-99
`and 102-104 obvious.
`Applicants respectfully disagree with the Examiner for the reasons set forth
`below. The law governing an obviousness rejection is recited in Applicants' Amendment dated
`December 20, 2013, and although not repeated here for the sake of brevity, is equally applicable
`to the present rejection.
`Applicants' claimed T cells are not "essentially disclosed by Milone" as the
`Examiner asserts, for all the reasons given above. Milone does not disclose T cells of a human
`having a cancer. Milone discloses human T cells from healthy donors. As discussed above, T
`cells from healthy donors are phenotypically different from T cells of cancer patients.
`Milone also does not disclose T cells comprising a CAR that includes a CD3zeta
`signaling domain comprising the amino acid sequence of SEQ ID N0:24.
`
`Miltenyi Ex. 1041 Page 11
`
`

`

`U.S. Application No. 13/938,923
`Amendment in response to fina l Office Action dated March 28, 2014
`
`Rosenberg does not cure the deficiencies of Milone. Rosenberg may disclose
`SEQ ID NOS: 16, 15 and 17 as components of a CAR, but Rosenberg does not teach or suggest
`the CAR of the present claims. Nowhere in Rosenberg is there a teaching ofT cells comprising
`a CAR as required by the present claims. In fact, nowhere in Rosenberg is there any suggestion
`or motivation to even make Applicants' CAR, let alone Applicants' CAR in T cells of a human
`having a cancer or an anti-tumor effective amount of T cells of a human having a cancer
`comprising Applicants' CAR.
`The combination of Milone in view of Rosenberg fails the first criterion of the
`KSR test, because one skilled in the art would not have found the requisite motivation or
`suggestion in Milone in view of Rosenberg so as to arrive at the present invention. Milone
`combined with Rosenberg simply teaches T cells obtained from healthy donors, not from a
`human having cancer, with different CARs therein that may be administered at a dosage with
`questionable efficacy to mice.
`The combination of Milone in view of Rosenberg also fails the second criterion
`of the KSR test, in that Milone in view of Rosenberg would not have prompted one skilled in the
`art to arrive at the present invention with a reasonable expectation of success. Milone does not
`teach Applicants' T cells and Rosenberg solely teaches sequences that may be used as
`components of Applicants' CAR. The combination of Milone and Rosenberg does not teach the
`skilled artisan how to generate an anti-tumor effective amount of T cells of a human having
`cancer as presently claimed. Absent Applicants' disclosure and impermissible hindsight, one
`skilled in the art would not have known how to arrive at the present invention, and thus the
`combination of prior art cited could not have motivated one skilled in the art to arrive at the
`present invention with a reasonable expectation of success.
`The combination of Milone in view of Rosenberg further fails the third criterion
`of the KRS test, because the prior art cited by the Examiner fails to teach or suggest all of the
`limitations of the present claims. Milone combined with Rosenberg teach different T cells
`having different CARs therein administered to mice with questionable efficacy in the mice.
`Nowhere in the combination of these two references can the present invention be found.
`
`5) Unexpected results - The Examiner states that Applicants' assertions and
`evidence are entirely directed to methods of treatment, whereas the claims at issue are directed to
`
`- 11 -
`
`Miltenyi Ex. 1041 Page 12
`
`

`

`U.S. Application No. 13/938,923
`Amendment in response to final Office Action dated March 28, 2014
`
`products. The Examiner's statement that clinical efficacy does not mitigate the instant rejections
`over the product claims appears to dismiss the evidence presented that the claimed
`pharmaceutical composition is unexpectedly better than prior art compositions simply because
`the claims are product claims.
`With aJI due respect, the Examiner misunderstands the law on obviousness and
`even fails to follow direction provided in the MPEP for patent examiners. Compositions can
`have unexpected properties. While properties of compositions are assessed through experimental
`methods, the Examiner impermissibly conflates the state of the law on the issue.
`The MPEP, citing Procter & Gamble Co. v. Teva Pharm. USA, Inc., 566 F.3d 989,
`90 USPQ2d 1947 (Fed. Cir. 2009) and referring to composition claims, states that:
`
`nonobviousness can be shown when a claimed invention is shown to have
`unexpectedly superior properties when compared to the prior art. MPEP § 2138
`(I )(B) Example 10.
`
`Further, in Bristol-Myers Squibb Co. v. Teva Pharms. USA , Inc., 752 F.3d 967
`(Fed. Cir. June 12, 2014), the co~ states:
`
`To be particularly probative, evidence of unexpected results must establish that
`there is a difference between the results obtained and those of the closest prior art,
`and that the difference would not have been expected by one of ordinary skill in
`the art at the time of the invention. Kao Corp. v. Unilever U.S., Inc., 441 F.3d
`963, 970 (Fed. Cir. 2006); see also Pfizer, 480 F.3d at 1371. Unexpected
`properties, however, do not necessarily guarantee that a new compound is
`nonobvious. While a "marked superiority" in an expected property may be
`enough in some circumstances to render a compound patentable, a "mere
`difference in degree" is insufficient. In re Papesch, 315 F.2d 381,392 (CCPA
`1963); In re Hoch, 428 F.2d 1341, 1344 n.5 (CCPA 1970) (explaining that
`unexpected "differences in properties" can mean "significant difference in degree
`of the same property" amounting to a "marked superiority" for purposes of
`evaluating unexpected results) (quotation omitted).
`
`Here, the pharmaceutical composition of the invention is markedly superior to
`prior art compositions. As evidenced by the accompanying D eclaration of Dr. Carl June being
`filed simultaneously herewith (hereinafter "June Declaration"), as of March 11, 2014, fifteen of
`thirty two adult patients with chronic lymphocytic leukemia (47 percent) responded to treatment
`with the claimed composition, where seven of those experienced a complete remission of their
`
`- 12 -
`
`Miltenyi Ex. 1041 Page 13
`
`

`

`U.S. Application No. 13/938,923
`Amendment in response to final Office Action dated March 28, 2014
`
`disease. Further, nineteen of twenty two pediatric patients with acute lymphocytic leukemia (86
`percent) experienced complete remission. The first pediatric patient treated with the protocol,
`who is now 8 years old, was in remission twenty two months after treatment in March 2014. She
`remains in remission today. All five of the first adult acute lymphocytic leukemia patients
`treated with the claimed composition thus far experienced complete remissions, the longest of
`which continues twelve months after treatment. Thus, the claimed compositions have properties
`that result in surprising therapeutic results in patients receiving the claimed compositions.
`Furthermore, Dr. June has received unprecedented awards and acclaim for the
`present invention. Such evidence is probative of non-obviousness under the law and must be
`considered by the Patent Office.
`As additional probative evidence of unexpected results, in July 7, 2014, the U.S.
`Food and Drug Administration granted CLT0 19, i.e., the composition of the present invention,
`"Breakthrough Therapy" status which means that this composition will be fast-tracked within the
`U.S. regulatory system. This represents the first cell-based composition comprising a chimeric
`antigen receptor to have achieved Breakthrough Designation from the U.S. Food and Drug
`Administration. See accompanying Reuters Press Release dated July 7, 2014.
`For all the reasons given, claims 97-99 and 102-104 are not obvious over Milone
`in view of Rosenberg and Applicants respectfully request that the rejection of these claims under
`35 U.S.C. § 103(a) be withdrawn.
`
`Reiection of Claims 100 and 105 under 35 U.S.C. § 103(a)
`Claims 100 and 105 have been rejected under 35 U.S.C. § 103(a) as allegedly
`being obvious over Milone as applied to claims 90-95, in view of Orentas et al.
`(WO20 13/059593; hereinafter "Orentas").
`As a first matter, claim 100 is canceled. Therefore, Applicants address this
`rejection as it applies solely to claim 105.
`Addressing the Examiner's statements regarding Applicants' arguments in the
`Amendment dated December 20, 2013:
`
`1) The Examiner notes that Applicants' statement that Milone does not teach
`autologous human T cells is false. Applicants traversal proffered above with respect to the
`
`- 13 -
`
`Miltenyi Ex. 1041 Page 14
`
`

`

`U.S. Application No. 13/938,923
`Amendment in response to final Office Action dated March 28, 2014
`
`rejection of claims 97-99 and 102-104 over Milone in view of Rosenberg, although not repeated
`here for the sake of brevity, are equally applicable. In any event, Milone does not teach
`Applicants' claimed T cells of a human having cancer and does not teach a CAR that includes a
`CD3zeta signaling domain comprising the amino acid sequence of SEQ ID N0:24.
`
`2) The Examiner argues that Milone provides a credible model of leukemia. As
`noted above, Applicants stand by their statement made in the Amendment filed December 20,
`2013.
`
`4) With regard to Applicants' arguments that Orentas does not cure the
`deficiencies in Milone, the Examiner asserts that "one cannot show nonobviousness by attacking
`references individually". Applicants do not understand the Examiner's reasoning. On page 11
`of the Amendment dated December 20, 2013, Applicants clearly address the Examiner's
`rejection by discussing the combination of Milone and Orentas - see fourth and fifth full
`paragraphs of page 11 of the Amendment.
`Applying the same logic as before, the Examiner concedes that Milone does not
`teach SEQ ID NO: 24 as the amino acid sequence of the CD3 zeta domain, but states that
`Orentas teaches this sequence as a component of a CAR. According to the Examiner, because
`Applicants' claimed T cells are "essentially those" disclosed by Milone, and Orentas teaches
`SEQ ID NO: 24 in a CAR, claims 100 and 105 are obvious over Milone in view of Orentas.
`Applicants respectfully traverse this rejection for several reasons including those
`discussed above with respect to the rejection of claims 97-99 and 102-104 over Milone in view
`of Rosenberg. The law governing an obviousness rejection is recited in Applicants' Amendment
`dated December 20, 2013, and although not repeated here for the sake of brevity, is equally
`applicable to the present rejection.
`Applicants' claimed T cells are not "essentially disclosed by Milone" as the
`Examiner asserts, for all the reasons given above. Milone does not disclose T cells of a human
`having a cancer. Milone discloses human T cells from healthy donors. As discussed above, T
`cells from healthy donors are phenotypically different from T cells of cancer patients.
`Milone also does not disclose a CAR comprising a CD3zeta signaling domain
`comprising the amino acid sequence of SEQ ID N0:24.
`
`- 14 -
`
`Miltenyi Ex. 1041 Page 15
`
`

`

`U.S. Application No. 13/938,923
`Amendment in response to final Office Action dated March 28, 2014
`
`Orentas does not cure the deficiencies in Milone, at least because, at the time of
`filing of the present application, Orentas did not teach or suggest SEQ ID NO:24 in a CAR. 1
`Further, Orentas does not teach Applicants' CAR or T cells comprising Applicants' CAR2
`.
`Nowhere in Orentas is there a teaching of T cells comprising a CAR as required by the pending
`claims. Nowhere in Orentas is there any suggestion or motivation to even make Applicants'
`CAR, let alone Applicants' CAR in T cells of a human having a cancer or an anti-tumor effective
`amount of T cells of a human having a cancer comprising Applicants' CAR.
`Milone combined with Orentas teach different T ceUs having different CARs
`therein administered to mice with questionable efficacy in the mice, and no reasonable
`expectation of success as an anti-tumor therapy in humans. Milone in view of Orentas fails all
`three criteria of the KSR test for the same reasons that Milone in view of Rosenberg fail.
`The claims are not obvious over Milone in view of Orentas and Applicants
`respectfully request that the rejection of claims 100 and 105 under 35 U.S.C. § 103(a) be
`reconsidered and withdrawn.
`
`5) Applicants' statements made herein with respect to unexpected results although
`not repeated for the sake of brevity are equally applicable here.
`
`1 Orentas does not teach or suggest SEQ ID NO:24 in the priority document that predates the disclosure of this
`sequence in the present application.
`
`2 Orentas does not teach or suggest SEQ ID NO:24 in the priority document that predates the disclosure of this
`sequence in the present application.
`
`- 15 -
`
`Miltenyi Ex. 1041 Page 16
`
`

`

`U.S. Application No. 13/938,923
`Amendment in response to final Office Action dated March 28, 2014
`
`Provisional Rejection of Claims 90-105 Under Non-Statutory Double Patenting
`
`Claims 90 and 92-105 have been provisionally rejected as being obvious over co(cid:173)
`
`pending Application Nos. 13/992,622 and 13/938,947 under the judicially created doctrine of
`
`double patenting. While Applicants neither agree or disagree with the Examiner regarding the
`
`merits of this rejection, Applicants request that the Examiner hold this rejection in abeyance
`
`until claims that the Examiner believes are in conflict are in fact deemed allowable.
`
`- 16 -
`
`Miltenyi Ex. 1041 Page 17
`
`

`

`U.S. Application No. 13/938,923
`Amendment in response to final Office Action dated March 28, 2014
`
`Summary
`
`Applicants respectfully submit that the amendments to the claims