Unrren States PATENT AND TRADEMARK OFFICE. ae SMSO ea 00 onnan016 oRSzT Ora OILS aot LeClairRyan (ALX) 2318 Mill Roa Suite 1100 Alexandria, VA 22314 RINT PAPER NONE Please find below and/or attached an Office communication concerning this application or proceeding. ‘The time period for reply, if any, is set in the attached communication PIOL-90A (Rev, 08107)UNITED STATEe PATENT AND TRADEMARIC OFFICE, a Trademark ce United State? DO NOT USE IN PALM PRINTER, (HRD PARTY REQUESTERS Cor *ONDENCE ADE WILMERHALE/EOSTON | 60 STATE STREET i BOSTON, MA 02109 EX PARTE REEXAMINATION COMMUNICATION TRANSMITTAL FORM REEXAMINATION CONTROL NO. 90:013,688. PATENT NO. 9181527 ART UNIT 3991, Enclosed is a copy of the latest communication from the United States Patent and Trademark Office in the above identified ex parte reexamination proceeding (37 CFR 1.550() Where this copy is supplied after the reply by requester, 37 CFR 1.535, or the time for filing a reply has passed, no submission on behalf of the ex parte reexamination requester will be acknowledged or considered (37 CFR 1.550()). PTOL-465 (Fev.07-04)ConirorNo- Patent Under Reexamination 90013686 9181527 Office Action in Ex Parte Reexamination | examiner Fat Unt Ria rst aventor io GARY KUNZ File) Status 3001 [No ~ The MAILING DATE of this communication appears on the cover sheet with the correspondence address ~~ 1B] Responsive tothe communicaton() fed on o2/na/s6 1 A ceciaration(syaidavit{s) under 37 CFR 1.190(b) was/were fled on D1 This action is made FINAL. ©. DB] Astatoment undor 37 CFR 1.590 has not been received from the patent ower. A shortened statutory period for response to this action is set to expite 2 month(s) from the mailing date ofthis leter. Failure to respond within the period for response will result in termination of the proceeding and issuance of an ex parte reexamination cartiicate in accordance with this action. 37 CFR 1.50(d). EXTENSIONS OF TIME ARE GOVERNED BY 37 CFR 1.550(c). Ifthe period for response specified above is less than thirty (30) days, a response within the statutory minimum of tity (30) days will be considered timely Part! THE FOLLOWING ATTACHMENT(S) ARE PART OF THIS ACTION: 1. C1 Notice of References Cited by Examiner, PTO-892 2. OD imerview summary, PTO-474 2. &] Information Disclosure Statement, PTO/SB/O8. 40 Part II SUMMARY OF ACTION ta. tb, Claims 1 ate subject to reexamination. Claims 2.23 are not subject to reexamination. Claims __ have been canceled in the present reexamination proceeding, Claims _are patentable andior confirmed. Claims 1 are rejected, Claime__are objected to, ‘The drawings, fledon __are acceptable. ‘The proposed drawing correction, fled on _has been (7a) C] approved (7b) disapproved, ‘Acknowledgment is made of the priority claim under 35 U.S.C. § 119(a)-(d) or (). a) BAI b) C) Some" c)[]None of the certified copies have 1 1 been received. BOOOBOORe 2D notbeen received 2 [been filed in Application No, 13/502,978 4 [1 been filed in reexamination Control No. __. 5 C1 been received by the international Bureau in PCT application No. * See the atached detailed Office action for alist ofthe ceriied copies not received 9. C1 Since the proceeding appears to be in condition for issuance of an ex parte reexamination certificate except for formal matters, prosecution as to the merits is closed in accordance with the practice under Ex parte Quayle, 1935 C.D. 11, 453 0.6, 213, 10.0) Other: cx (if third party requester) PTOL-466 (Rev. 08-18) Office Action in Ex Parte Reexamination Par of Paper No. 2016061 1Application/Control Number: 90/013,688 Page 2 Art Unit: 3991 Ex Parte Reexamination: Non-Final Action Procedural Posture November 10, 2015: _U. S. Patent Application No. 13/502,978 filed October 29, 2012 issued to Charles L. Sentman as U. S. Patent No. 9,181,527 ("Sentman '527"). February 10,2016: Third Party Requester filed a request for ex parte reexamination of claim 1 of Sentman ‘527. Information Disclosure Statement (IDS) The documents cited on the Information Disclosure Statements (IDS) filed January 27, 2016 and February 10, 2016 have been considered. An initialed, signed copy of these IDS's accompany this Office Action. Claim Under Reexamination Claim 1 is the only claim under reexamination because the Third Party Requester asked that only claim 1 of the Sentman ‘527 patent be reexamined in the Request filed February 26, 2015. Accordingly, claims 2 - 23 are not under reexamination, The Sentman ‘527 Invention The invention of Sentman '527 is directed to an isolated modified primary human T cell with functionally impaired or reduced expression of the endogenous T cell receptor and further modified to express a functional non-exogenous T-cell receptor that is a chimeric receptor comprising a ligand binding domain attached to a signaling domain. The chimeric receptor is suitable for human therapy and elicits no or a reduced graft-versus-host response. Claim 1 is reproduced below:Application/Control Number: 90/013,688 Page 3 Art Unit: 3991 Claim 1. An isolated modified primary human T-cell, which is derived from a primary human T cell isolated from the human donor, that: (i)_ is modified to functionally impair or reduce expression of the endogenous T cell receptor (TCR), and (ii) is further modified to express at least one functional exogenous non-TCR that comprises a chimeric receptor comprising a ligand binding domain attached to a signaling domain, wherein said modified primary human T cell is suitable for use in human therapy, and further wherein the isolated primary human T cell modified as in (i) and (ii) elicits no or a reduced graft-versus- host disease (GVHD) response in a histoincompatible human recipient as compared to the GVHD. response elicited by a primary human T cell isolated from the same human donor that is only modified as in (ii). References Cited by Requester 1. Imaiet al, (2004), “Genetic modification of T cells for cancer therapy,” J. Biol. Regu. Homeost. Agents 18: 62 — 71 (“Imai”). 2. Kambayashi et al. (2001), “IL-2 down regulates the expression of TCR and TCR- associated surface molecules on CD8+ T cells,” Eur. J. Immunol. 31: 3248 ~ 3254 (“Kambayashi”) 3. Chan et al. (2006), “Single-Cell Analysis of siRNA-Mediated Gene Silencing Using Multiparameter Flow Cytometry,” Cytometry, Part A, 69(2): 59 ~ 65 (“Chan”), 4. Okamoto et al. (December 1, 2009), “Improved Expression and Reactivity of Transduced ‘Tumor-Specific TCRs in Human Lymphocytes by Specific Silencing of Endogenous TCR,” Cancer Research 69(23): 9003 — 9011 (“Okamoto”). Imai & Campana, Kambayashi and Chan were not of record and were not considered by the examiner during the prosecution of the application that issued as Sentman '527. Applicant cited Okamoto in the IDS filed May 11, 2015 and was discussed by the Examiner in the Office Action mailed August 17, 2015 as part of a lack of enablement rejection. However, Okamoto is now being viewed in new and different light when combined with Imai & Campana.Application/Control Number: 90/013,688 Page 4 Art Unit: 3991 References cited by Examiner 1. Mineno et al., WO 2008/153029 published December 18, 2008 (“Mineno”’). 2. Wuetal., “A Functional T-Cell Receptor Signaling Pathway Is Requi Activity,” Mol. Cell. Biol. August, 1994, pages 4337 — 4346 ("Wu"). d for pas Claim Interpretation The phrases "functional endogenous TCR” and "functional exogenous non-TCR" appear in instant claim 1, However, nowhere in the specification of Sentman ‘527 does the Patent Owner define a “functional endogenous TCR” or a “functional exogenous non-TCR Consequently, it is appropriate to look to extrinsic evidence such as in Wu et al. (A functional T- cell receptor signaling pathway is required for p95 vav activity,” Mol. Cell Biol. 15(8): 4337 - 4346) Wu et al. explains that a functional endogenous TCR is interpreted to be a naturally occut 1g TCR that is capable of both binding a spe ic ligand to the extracellular domain of the receptor and then transducing that binding to a signal within the cell that induces the activation of multiple tyrosine kinases, resulting in phosphorylation of numerous intracellular substrates (Wu et al., Abstract) Similarly, “a functionally exogenous non-TCR” is interpreted to be a non- naturally occurring TCR, that is capable of binding a specific antigen that is different from the specific ligand that functionally endogenous TCRs bind, and transducing the binding of this specific ligand into the cell through the activation of multiple tyrosine kinases, also resulting in phosphorylation of numerous intracellular substrates (Wu et al.) To “functionally impair” an endogenous TCR is interpreted to prevent or inhibit the expression of the ligand binding extracellular domain in order to prevent a GVHD responseApplication/Control Number: 90/013,688 PageS Art Unit: 3991 (Imai at page 67, right column, last paragraph). Statutory Basis for Claim Rejections - 35 USC 103(a) The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action: (a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of ths tit, i the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill n the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made. Claim 1 is rejected under 35 USC 103(a) as being unpatentable over Imai and Mineno. Imai is a review article that summarizes the development of immunotherapies for cancer using modified T cells. Imai teaches that "[Glenetically-modified T lymphocytes are a promising agent for the treatment of cancer” (page 66, right column, third paragraph). Imai explains that methods have been developed to redirect the specificity of primary T cells to express exogenous T cell receptors (TCR), i.e., TCR’s which are introduced into the T cells by genetic engineering (Abstract, page 62, right column, second paragraph). Imai discusses that Eshar established that chimeric receptors composed of antigen-specific scFv and intracellular signaling molecules could mediate target-specific cytotoxicity of lymphocyte mouse hybridoma cells. Such a chimeric receptor directs cytotoxicity mediated by primary lymphocytes has been demonstrated for a wide range of antigens (page 63, right column, second paragraph). Imai emphasizes that the presence of an exogenous modified TCR by itself is not sufficient to trigger T-cell activation upon binding to an epitope-presenting cancer cells (page 64, right column first paragraph, Fig, 1). The chimeric receptor must also possess an intracellular signalingApplication/Control Number: 90/013,688 Page 6 Art Unit: 3991 transduction molecule that can activate T-cells (Id.). Consequently, the primary T cells must be transduced with DNA that is a chimera of an extracellular epitope-recognition component and an intracellular signal transduction molecule that can activate T cells ({d.). Thus, Imai discloses the limitations in the preamble and section (ii) in claim 1 along with the subsequent requirement that the modified primary T cells are suitable for use in human therapy as shown below in bold typeface: Claim 1. An isolated modified primary human T-cell, which is derived from a primary human T cell isolated from the human donor, that: (i)_ is modified to functionally impair or reduce expression of the endogenous T cell receptor (TCR), and further modified to express at least one functional exogenous non-TCR that ‘comprises a chimeric receptor comprising a ligand binding domain attached toa signaling domain, wherein said modified primary human T cell is suitable for use in human therapy, and further wherein the isolated primary human T cell modified as in (i) and (i elicits no or a reduced graft-versus-host disease (GVHD) response in a histoincompatible human recipient as compared to the GVHD response elicited by a primary human T cell isolated from the same human donor that is only modified asin (i) Imai also recognized the need to reduce the risk of severe GvHD caused by the continued expression of endogenous TCR by transduced lymphocytes, i.e, part (i) of claim 1 above (page 67, right column, last paragraph). Imai even suggested that “[FJuture studies should also determine the feasibility and consequences of chimeric receptor expression in TCR negative, non-GvHD promoting cytotoxic cells, such as CD3-negative natural killer cells” (Id.) However, Imai fails to teach how to modify or functionally impair or reduce expression of the endogenous T cell receptor (TCR) as in section (i) above and to eliminate or reduce a graft- versus-host response in a histoincompatible human recipient as compared to a similar responseApplication/Control Number: 90/013,688 Page 7 Art Unit: 3991 elicited by primary human T cells isolated from the same human donor that is modified as in section (ii) Mineno discloses a cell expressing a non-natural T cell receptor, i.e. exogenous non-TCR, that is “modified to functionally impair or to reduce expression of endogenous T cell receptor (TCR)” by using two siRNAs, one which inhibits the expression of the endogenous a-polypeptide chain of the natural TCR and the other which inhibits the expression of the endogenous B- polypeptide chain of the natural TCR by RNA interference” (Mineno at paragraphs [0038] and [0039]. This reduction in the expression of the endogenous TCRs produced by the siRNAs will necessary result in the concluding limitation of claim 1: and further wherein the isolated primary human T cell modified as in (i) and (i) elicits no or a reduced graft-versus-host disease (GVHD) response in a histoincompatible human recipient as compared to the GVHD response elicited by a primary human T cell isolated from the same human donor that is only modified asin (i) Mineno also teaches that the cell is also modified with recombinant nucleic acid sequences which encode exogenous a and B polypeptide chains that constitute the non- natural TCR and that correspond to the cell's endogenous @ and B polypeptide chains that constitute the cell’s natural TCR having a variable region and a constant region. However, the amino acid sequence of the exogenous a and B polypeptide chains partially differ from that of the endogenous a and B polypeptide chains of the endogenous a and B polypeptide chains of the natural TCR and are not inhibited by the siRNAs (Examples 3 and 6). Accordingly, the cell “is further modified to express at least one functional exogenous non-TCR that comprises a chimeric receptor comprising aApplication/Control Number: 90/013,688 Page8 Art Unit: 3991 ligand binding domain attached to a signaling domain.” See paragraphs (007}, [0011], [0024] and [0025] of Mineno. It would have been obvious to a person of ordinary skill in the art at the time of the invention to have altered the T cells of Imai modified to express a functional exogenous TCR while inhibiting the expression of a function endogenous TCR as taught by Mineno and recognized by Imai as necessary to reduce the risk of severe GVHD caused by the continued expression of endogenous TCR by transduced lymphocytes, i.e., part (i) of claim 1 above (page 67, right column, last paragraph). Imai even suggested that “[FJuture studies should also determine the feasibility and consequences of chimeric receptor expression in TCR negative, non-GvHD promoting cytotoxic cells, such as CD3-negative natural killer cells” (/d.) This different expression of the functional exogenous non-TCR while inhibiting the expres: n of functional endogenous TCRs is accomplished by introducing two siRNAs that inhibit the expression of the functional endogenous TCR while permitting the expression of the chimeric exogenous TCR as taught by Mineno (paragraphs [0039] and [0040]; Examples 3 and 9) ‘There is a reasonable expectation of success in transferring the technique of Mineno for selectively inhibiting the expression of endogenous T-cell receptors in genetically modified human peripheral blood mononuclear cells (HPBMC) to genetically modified human T-cell lymphocytes as taught because the fundamental basis of genetic modification of and selective inhibition of endogenous T-cell receptors using siRNA remains the same.Application/Control Number: 90/013,688 Page 9 Art Unit: 3991 Finally, the inhibition of the expression of functional endogenous TCR will necessarily result in the reduction of elimination of graft-versus-host disease (GvHD) as required by the concluding limitati of claim 1 as taught by Imai at page 67, right column, last paragraph. Accordingly, claim 1 is prima facie obvious over Imai and Mineno. References Not Used in a Claim Rejection Kambayashi was not used in a claim rejection along with Imai & Campana because this reference fails to selectively inhibit the expression of endogenous TCRs without inhibiting the expression of exogenous TCRs. The inhibition of both functional endogenous TCRs as welll as functional exogenous TCRs does not produce the required cell modification~little or no functional endogenous TCRs while permitting full expression of a functional exogenous TCR. Okamoto was not used in a claim rejection because Okamoto is not prior art against claim 1 of Sentman ‘527. Okamoto was published on November 10, 2009, after the earliest effective priority date of Sentman '527, October 18, 2009. In addition, the Mineno et al. document contains the same information as in Okamoto but has a publication date (December 18, 2008) that is much earlier than the publication date for Okamoto. Chan was not used in a claim rejection along with Imai & Campana because Chan did not actually demonstrate the selective inhibition of the expression of T-cell receptors with siRNA while leaving unaffected the expression of exogenous receptors. Conclusion Claim 1 is rejected. Claims 2 - 23 are not under reexamination. (see MPEP § 2240).Application/Control Number: 90/013,688 Page 10 Art Unit: 3991 Extensions of time under 37 CFR 1.136(a) do not apply in reexamination proceedings. The provisions of 37 CFR 1.136 apply only to “an applicant” and not to parties ina reexamination proceeding. Further, in 35 U.S.C. 305 and in 37 CFR 1.550(a), it is required that reexamination proceedings “will be conducted with special dispatch within the Office.” Extensions of time in reexamination proceedings are provided for in 37 CFR 1.550(c). A request for extension of time must specify the requested period of extension and it must be accompanied by the petition fee set forth in 37 CFR 1.17(g). Any request for an extension in a third party requested ex parte reexamination must be filed on or before the day on which action by the patent owner is due, and the mere filing of a request will not effect any extension of time. A request for an extension of time in a third party requested ex parte reexamination will be granted only for sufficient cause, and for a reasonable time specified. Any request for extension in a patent owner requested ex parte reexamination (including reexamination ordered under 35 U.S.C. 257) for up to two months from the time period set in the Office action must be filed no later than two months from the expiration of the time period set in the Office action. A request for an extension in a patent owner requested ex parte reexamination for more than two months from the time period set in the Office action must be filed on or before the day on which action by the patent owner is due, and the mere filing of a request for an extension for more than two months will not effect the extension. The time for taking action in a patent owner requested ex parte reexamination will not be extended for more than two months from the time period set in the Office action in the absence of sufficient cause or for more than a reasonable time. The filing of a timely first response to this final rejection will be construed as including a request to extend the shortened statutory period for an additional two months. In no event, however, will the statutory period for response expire later than SIX MONTHS from the mailing date of the final action. See MPEP § 2265. Ongoing Duty to Disclose The patent owner is reminded of the continuing responsibility under 37 CFR 1.565(a) to apprise the Office of any litigation activity, or other prior or concurrent proceeding, involving Patent No, 9,181,527 B2 throughout the course of this reexamination proceeding. The third party requester is also reminded of the ability to similarly apprise the Office of any such activity or proceeding throughout the course of this reexamination proceeding.Application/Control Number: 90/013,688 Page 11 Art Unit: 3991 Future Amendment Patent owner is notified that any proposed amendment to the specification and/or claims in this reexamination proceeding must comply with 37 CFR 1.530(d)-(j), must be formally presented pursuant to 37 CFR 1.52(a) and (b), and must contain any fees required by 37 CFR 1.20(c). Submission of amendments, affidavits or declarations, or other documents as evidence of patentability in response to this FINAL ACTION will be governed by the requirements of 37 CFR 1.116, which will be strictly enforced. Service of Papers After the filing of a request for reexamination by a third party requester, any document filed by either the Patent Owner or the Third Party Requester must be served on the other party (or parties where two or more third party requester proceedings are merged) in the reexamination proceeding in the manner provided in 37 CFR 1.248. Further Correspondence Any inquiry concerning this communication or earlier communications from the examiner should be directed to Gary L. Kunz, whose telephone number is 571-272-0887. The examiner can normally be reached on Monday through Friday between 10:00 AM and 7:30 PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner's, supervisor, Jean Witz, can be reached at 571-272-0927. The fax phone number for the organization where this application or proceeding is assigned is 571-273-9900, Information regarding the status of an application may be obtained from the PatentApplication/Control Number: 90/013,688 Page 12 Art Unit: 3991 Application Information Retrieval (PAIR) system. Status information for unpublished applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIBR system, see http://pair-direct.uspto.gov. Should you have questions about access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll- free), All correspondence relating to this Ex parte Reexamination proceeding should be directed to: By Electronic Filing System (EFS: Registered users may submit via the electronic filing system EPS-Web at https://efs.uspto.gov/efile/myportal/efs-registered By Mail to: Attn: Mail Stop “Ex Parte Rexam” Central Reexamination Unit Commissioner of Patents P.O. Box 1450 Alexandria, VA 22313-1450 By FAX to: (571) 273-9900 Central Reexamination Unit By hand t Customer Service Window Randolph Building 401 Dulany Street Alexandria VA 22314Application/Control Number: 90/013,688 Page 13 Art Unit: 3991 For EFS-Web transmissions, 37 CFR 1.8(a)(1)(i)(C) and (ii) states that correspondence (except for a request for reexamination and a corrected or replacement request for reexamination) will be considered timely filed if (a) it is transmitted via the Office’s electronic filing system in accordance with 37 CFR 1.6(a)(4), and (b) includes a certificate of transmission for each piece of correspondence stating the date of transmission, which is prior to the expiration of the set period of time in the Office Action. [Gary L. Kunz/ /Padmashri Ponnaluri/ Patent Reexamination Specialist Patent Reexamination Specialist CRU Art Unit 3991 CRU Art Unit 3991 [ean C. Wite/ Supervisory Patent Reexamination Specialist CRU 3991