Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Amendments
In the reply filed 11/18/2025, Applicant has amended Claims 151, 153, 154, and 159.
Claims 159-167 are pending but withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Claims 151-158 are under consideration.
Election/Restrictions
Applicant’s election of the following species without traverse in the reply filed on 5/20/2025 has been acknowledged.
NK cells as the species of immune cell.
CD70 as the tumor antigen recognized by the CAR.
Applicant is reminded as stated in MPEP 819 that the general policy of the Office is that Applicants are not permitted to shift to claim another invention after an election is made and an Office action on the merits is made on the elected invention. Specifically, the Applicant may not disaffirm or change their election, as a matter of right, after making an election and receiving an Office action based upon that election in a pending application. See 37 CFR 1.142(b), see also MPEP § 706.07(h), subsection VI.(B).
Nevertheless, in light of the shift resulting no significant additional burden and simplifying the issues, the Examiner has permitted this shift in invention. MUC-1 as the tumor antigen is rejoined.
Priority
The instant application was filed 2/17/2022 and is a divisional of application 19/900,372 filed 6/12/2020, which is a continuation of application 16/180,867 filed 11/05/2018, which is a continuation of application 15/224,151 filed 07/29/2016, which claims priority to provisional applications 62/360,245 filed 07/08/2016, 62/330,464 filed 05/02/2016, 62/295,670 filed 02/16/2016, 62/286,206 filed 01/22/2016, 62/232,983 filed 09/25/2015, and 62/199,905 filed 07/31/2015
Review of the prior filed applications did not reveal support for a cell comprising a genomic disruption in a CISH genomic target sequence until provisional application 62/286,206 filed 1/22/2016.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 11/18/2025 was filed after the mailing date of the non-final Office action on 6/18/2025. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Withdrawn Claim Rejections - 35 USC § 112(a)
The prior rejection of Claims 151-158 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is withdrawn in light of Applicant’s amendments to no longer recite CD70 as the tumor antigen.
Withdrawn Claim Rejections - 35 USC § 112(b)
The prior rejection of Claim 153 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn in light of Applicant’s amendment of instant claim to describe the insertion site.
Withdrawn 35 USC § 103
The prior rejection of Claims 151-158 under 35 U.S.C. 103 as being unpatentable over Duchateau et al., (US 2018/0171298, filed 6/30/2016, with priority to PA201570408 filed 6/30/2015), in view of Huntington et al., (US 2018/0298101, filed 12/16/2016, with priority to AU2015905220, see IDS filed 7/27/2022) is withdrawn in light of Applicant’s amendment of Claim 151 to no longer include CD70 as the tumor antigen.
New Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102 of this title, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 151-158 are rejected under 35 U.S.C. 103 as being unpatentable over Duchateau et al., (US 2018/0171298, filed 6/30/2016, with priority to PA201570408 filed 6/30/2015), in view of Huntington et al., (US 2018/0298101, filed 12/16/2016, with priority to AU2015905220, see IDS filed 7/27/2022), Jones et al., (US 2019/0030151, filed 1/13/20176, with priority to US provisional 62/279,275 filed 1/13/2016), and Wilkie et al. (J Immuno, 2008, 180:4901-4909)
In regard to claim 151, Duchateau teaches a pharmaceutical composition comprising
Population of genetically modified NK cells for the treatment of cancer comprising
A genomic disruption by a programmable nuclease in a checkpoint gene target sequence (p. 4-5, Summary of invention of priority document),
An exogenous CAR that targets the tumor antigen (p. 6, Summary of invention, pgs. 29-30 of priority document); and
A pharmaceutically acceptable carrier.
However, in regard to claim 151 (a)(i), Duchateau is silent with respect to the checkpoint being CISH.
Nevertheless, in regard to instant claims Huntington et al already taught using Cytokine-induced SH2 protein (CISH)-inhibited NK cells for treating a subject suffering from a cancer (e.g., metastatic melanoma, metastatic breast cancer, brain cancer, liver cancer), wherein the CIS-inhibited NK cells are NK cells that are genetically modified to have reduced expression of CIS via gene editing with programmable nucleases (e.g., the CRISPR-Cas system that is very efficient and routinely used for targeted disruption of gene) (Abstract; Summary of the Invention; particularly page 2-3; page 31 of priority document). Huntington et al demonstrated that CISH-null NK cells are hyper-sensitive to IL-15, with superior proliferation and cytotoxicity in comparison with Cish+/+ NK cells; and these results suggest that CISH acts as an immune checkpoint controlling NK cell responses (Example 3 at pages 66-67 of priority document). Huntington et al also demonstrated that adoptive transfer of Cish-/- NK cells in mouse tumor models results in significantly reduced tumor formation and metastasis (Example 8); and adoptive transfer of Cish-/- NK cells in a mouse melanoma model is more effective than anti-PD-1/CTLA-4 immunotherapy alone, and has greater efficacy in combination with anti-PD-1/CTLA-4 immunotherapy (Example 9).
Accordingly, it would have been obvious for an ordinary skilled artisan before the effective filing date of the present application to modify the teachings of Duchateau et al by also further editing/deleting the endogenous CISH gene to improve NK cell cytotoxic/cytolytic activity via editing/disrupting the endogenous CISH gene, in light of the teachings of Huntington et al as presented above.
The modified genome-edited NK cell resulting from the combined teachings of Duchateau et al, and Huntington et al as set forth above is indistinguishable from and encompassed by the genome-edited primary NK cell of the present application,
An ordinary skilled artisan would have a reasonable expectation of success to achieve genetic modification in the majority of NK cell population in light of the teachings of Duchateau et al, and Huntington et al; coupled with a high level of skill for an ordinary skilled artisan in the relevant art.
However, in regard to claim 151 (a)(ii), Duchateau is silent with respect to the CAR targeting MUC1.
In regard to claim 151 (a)(ii), Jones suggests a pharmaceutical composition comprising
Population of genetically modified immune cells comprising NK cells ([0082, 0097, 0124] of priority document), which comprise:
A genomic disruption mediated by a nuclease in a checkpoint gene ([0073, 00106], see also Claim 28 priority document),
An exogenous CAR that targets the tumor antigen MUC1 ([0006-0007, 0013, 0047, 0082, 0097], see Claim 17 of priority document); and
A pharmaceutically composition thereof ([0013, 00131, 0155-0156], see Claims 35 and 65 of priority document).
Accordingly, it would have been obvious for an ordinary skilled artisan before the effective filing date of the present application to modify the teachings of Duchateau et al by choosing an anti-MUC1 CAR as taught by Jones with a reasonable expectation of success. One of ordinary skill the art would have been motivated to do so as taught by Wilke et al. (2008), who teaches that MUC1 is a highly attractive immunotherapeutic target owing to increased expression in greater than 80% of human cancers (Abstract, Introduction, 2nd para. Discussion, 1st para.). In regard to the reasonable expectation of success in doing so, Wilke provides an enabling disclosure for making an anti-MUC1 CAR that could be used in the NK cells suggested by Duchateau and Jones (p. 4902, Materials & Methods), and teaches NK cells with an anti-MUC1 TCR protected against MUC1+ xenografts (Discussion, last para.).
In regard to claims 152 and 153, Duchateau teaches that the exogenous nucleic acids are integrated (p. 36, 3rd para.), and both Duchateau and Huntington teach site directed nucleases and how to target specific genes. Thus, it would have been obvious to target the exogenous CAR to the TCR gene or CISH gene with a reasonable expectation of success. One would have been motivated to do so for several reasons. First, targeted integration avoids the off-target effects of insertional mutagenesis, but allows the CAR to be stably expressed for the life of the cell (p. 2, 2nd para., p. 36, 3rd para. of Duchateau). Furthermore, in regard to claim 152, since NK cells do not express the TCR genes, these loci would act as safe harbors for the exogenous CAR. Furthermore, in regard to claim 153, Jones suggests that the “transgene can be inserted such that the insertion disrupts a gene, e.g., and endogenous immune checkpoint” ([0073] of priority document), which again would act as a safe harbor locus for the exogenous CAR.
In regard to claim 155, it was well known that NK cells express CD56, and both Duchateau and Huntington teach purifying CD56 positive NK cells (p. 23, 1st para. of Duchateau, p. 32, 2nd para. of Huntington).
In regard to claims 156 and 157, Duchateau teaches the NK cells are human primary cells from PBMCs (p. 38, 1st para., p. 51 Example 1), which fulfills the intended use of “autologous”. Furthermore, Jones also suggests the NK cells are human primary cells from peripheral blood lymphocytes ([0042, 0124, 0127] of priority document), and are to fulfill the intended use of “autologous” transplantation ([0013, 0047-0048] of priority document), and Huntington teaches CISH-/- autologous NK cells for use in adoptive cell therapy (p. 27, 1st para. of priority document), thereby making it predictably obvious to prepare a composition of autologous human NK cells. Finally, in regard to claim 157, all cells in the human body were initially derived from pluripotent stem cells.
In regard to claim 158, as stated supra, both Duchateau and Huntington teach using CRISPR-Cas for the efficient disruption of the checkpoint gene (i.e., CISH), see also Jones use of CRISPR/Cas nuclease for specific integration of nucleic acids ([0106, 0116] of priority document). Thus, one could have performed TIDE analysis. Please note that where, as here, the claimed and prior art products are identical or substantially identical, or are produced by identical or substantially identical processes, the PTO can require an applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his claimed product. See In re Ludtke. Whether the rejection is based on "inherency" under 35 USC 102, or "prima facie obviousness" under 35 USC 103, jointly or alternatively, the burden of proof is the same, and its fairness is evidenced by the PTO's inability to manufacture products or to obtain and compare prior art products. In re Best, Bolton, and Shaw, 195 USPQ 430, 433 (CCPA 1977) citing In re Brown, 59 CCPA 1036, 459 F.2d 531, 173 USPQ 685 (1972).
Therefore, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
RESPONSE TO ARGUMENTS
Applicant's arguments filed on 11/18/2025 are acknowledged.
Applicant argues that none of the cited prior art teaches an exogenous CAR or TCR that targets the MUC1 tumor antigen.
Applicant's arguments have been fully considered and they are found persuasive. However, a new rejection has been made in view of Jones and Wilke who suggest an anti-MUC1 CAR to be expressed in a NK cell.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ARTHUR S LEONARD whose telephone number is (571)270-3073. The examiner can normally be reached on Mon-Fri 9am-5pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James Doug Schultz can be reached on 571-272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ARTHUR S LEONARD/Examiner, Art Unit 1631