DETAILED ACTION
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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 02 September 2025 has been entered.
Status of the Claims
Applicant’s submission filed 02 September 2025 has been entered. Claims 1-6, 9-18, and 21 are pending. Claim 1 has been amended. Therefore, prosecution on the merits continues for claims 1-6 as being drawn to the elected invention, while claims 9-18 and 21 are withdrawn for reading on non-elected invention(s). All arguments have been fully considered with the status of each prior ground of rejection set forth below.
Status of Prior Rejections/Response to Arguments
RE: Objection to claim 1
Applicant’s amendments to independent claim correct the minor informalities, thus obviating the objections of record.
Therefore, the objections are withdrawn.
RE: Rejection of claims 1-3 and 6 under 35 USC 102(a)(2) over Jensen et al
Applicant has traversed the rejection, asserting in Page 6 of the Remarks filed 02 September 2025 that Jensen et al do not disclose a method wherein the T cells are transduced with the same chimeric antigen receptor (CARs), and instead disclose that the first and second CARs can be specific for the same target antigen but have different ligand binding domains. In response, the Examiner has fully considered these arguments and has found them persuasive.
Therefore, the rejection is withdrawn.
It is of note, however, that Applicant’s arguments in Pages 6-7 regarding the lack of a selection step within the method fail to comply with 37 CFR 1.111(b) because they amount to a general allegation that the claims define a patentable invention without specifically pointing out how the language of the claims patentably distinguishes them from the references.
RE: Rejection of claims 1-3 and 5-6 under 35 USC 103 over Jensen et al
Applicant has traversed the rejection, citing the same assertions as discussed above in regards to Jensen et al within Pages 6-7 of the Remarks filed 02 September 2025. In response, the Examiner respectfully directs Applicant to the discussion of the 35 USC 102 rejection over Jensen et al.
Therefore, the rejection is withdrawn.
RE: Rejection of claims 1-6 under 35 USC 103 over Jensen et al in view of Jensen
Applicant has traversed the rejection, citing the same assertions as discussed above in regards to Jensen et al within Pages 6-7 of the Remarks filed 02 September 2025. In response, the Examiner respectfully directs Applicant to the discussion of the 35 USC 102 rejection over Jensen et al.
Therefore, the rejection is withdrawn.
New Grounds of Rejection
Claim Interpretation
The instant disclosure defines the term “activity modulator” as a molecule made by the
CAR-expressing cell which modulates the activity of the CAR, of a cell expressing the CAR, or of a target
cell. See Page 41 of the instant Specification filed 07 March 2025.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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, 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 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 1, 4, and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Bedoya et al (US 2017/0137783) in view of Yang et al (US 2012/0134970 A1) and Ma et al (US 2018/0066034 A1).
Each of Bedoya et al, Yang et al, and Ma et al are considered prior art under 35 USC 102(a)(1) and 35 USC 102(a)(2).
Regarding claims 1 and 6: Bedoya et al disclose methods of making immune effector cells that can be engineered to express a chimeric antigen receptor (CAR), and reaction mixtures comprising the same (Abstract).
As such, Bedoya et al disclose a method of forming a reaction mixture, wherein a population of immune effector cells are transduced with viral vectors comprising nucleic acids encoding a first CAR and a second CAR under control of an inducible or constitutive promoter such that the CARs are integrated into the genome of the cell, wherein the first CAR and second CAR are the same CAR (Paragraphs [0020], [0032], [0043], [0045], [0048], [0068]-[0070], [0077], [0080], [0109]-[0111], [0309], [0315]-[0316], [0335]-[0336], [0441], [0458]-[0459], [0574], [0576]-[0582]). Bedoya et al further disclose that the first and second CARs comprise antigen binding domains specific for tumor antigens (Paragraphs [0021], [0087]-[0088], [0114]-[0119], [0242], [0336], [0441]-[0442]).
Bedoya et al further disclose that the population of immune effector cells within the reaction mixture can express the first CAR and the second CAR simultaneously (overlapping) or sequentially (Paragraphs [0048], [0077]).
Bedoya et al further disclose that a viral vector comprising an encoded CAR can further comprise a nucleic acid encoding an activity modulator that is operably linked to the CAR (Paragraphs [0561]-[0565]).
Bedoya et al do not explicitly disclose that the first CAR and second CAR are comprised within separate viral vectors, as required by instant claim 1.
Yang et al, however, disclose methods for creating viral vector nucleic acid sequences, wherein nucleic acids encoding the same chimeric immune receptors are comprised within separate viral vectors under control of either an inducible or constitutive promoter and co-transduced into immune effector cells, and wherein the chimeric immune receptors comprise target binding domains specific for tumor antigens (Abstract; Paragraphs [0015]-[0016], [0024]-[0025], [0033]-[0036], [0041], [0043]-[0049], [0052], [0062]-[0064], [0069]-[0070], [0085], [0108], [0115], [0117], [0127], [0138], [0149], [0157], [0159]-[0164], [0167]-[0169], [0173]-[0177], [0183], [0206]-[0207], [0210], [0232], [0251], [0255]).
With that, Ma et al generate immune cells expressing CARs, wherein the immune cells are transduced twice with a lentiviral vector encoding the same CAR. Ma et al further show double transduced T cells expressing an anti-CD5 CAR have decreased surface expression of CD5 compared to single transduced T cells expressing the anti-CD5 CAR (Paragraphs [0057]-[0058], [0303]; Figures 17-18). Thus, Ma et al establish that expressing the same CAR from two different vectors in the same immune cell increases the functional effect of a CAR.
Therefore, it would have been prima facie obvious to have modified the method of Bedoya et al such that the first and second CARs are comprised within separate viral vectors, and co-transduced as detailed in Yang et al. More specifically, it would have been prima facie obvious to combine Bedoya et al with Yang et al because Bedoya et al disclose the co-expression of the same CAR in an immune cell, wherein the CARs are encoded on viral vectors, and Yang et al disclose the co-transduction of viral vectors encoding the same chimeric immune receptors in immune cells. See MPEP § 2143(I)(A). Furthermore, one of ordinary skill in the art before the effective filing date of the invention would have been motivated to have the same CARs encoded within separate vectors for co-transduction, because Ma et al demonstrate expressing the same CAR from two separate vectors in a cell results in the increased functional effect of the expressed CAR. See MPEP § 2143(I)(G). The ordinary artisan would have had a reasonable expectation of success given that the disclosures of Bedoya et al and Yang et al are concerned with the transduction of immune effector cells with vectors comprising the same chimeric receptor and their co-expression, and Ma et al demonstrate co-expression of the same CAR increased a functional effect of the CAR.
Consequently, Boyega et al as modified by Yang et al and Ma et al render obvious a method of transducing cells with two viral vectors (claim 6) to form a reaction mixture, wherein a first viral vector comprises a nucleic acid encoding a CAR and activity modulator, while a second viral vector comprises a nucleic acid encoding the same CAR. As the reaction mixture is a heterogeneous population of immune effector cells comprising either the first CAR and/or the second CAR, this therefore renders obvious the method of instant claim 1.
Regarding claim 4: Following the discussion of claim 1, Boyega et al further disclose that the nucleic acid encoding the CAR can be operably linked to a nucleic acid encoding a chimeric chemokine receptor (Paragraph [0569]). As the chimeric chemokine receptor and CAR are under control of the same promoter (Paragraph [0569]), and the CAR can be under control of a constitutive promoter such that it is constitutively active (Paragraphs [0315], [0576], [0582]), this therefore renders obvious the method of the instant claim for the same reasons as discussed in the rejection of instant claim 1.
Claims 1-6 are rejected under 35 U.S.C. 103 as being unpatentable over Bedoya et al (US 2017/0137783) in view of Yang et al (US 2012/0134970 A1) and Ma et al (WO 2016/138491 A1), and further in view of Jensen et al (US 2020/0181624 A1, of record).
The discussion of Bedoya et al in view of Yang et al and Ma et al regarding claim 1 can be observed above and is relied upon herein, the content of which is incorporated in its entirety. Bedoya et al as modified by Yang et al and Ma et al render obvious claims 1, 4, and 6. Jensen et al is considered prior art under 35 USC 102(a)(2), with an effective filing date of 12 December 2016.
Regarding claims 2-3: As aforementioned in the discussion of claim 1 above, Bedoya et al disclose a viral vector comprising a nucleic acid sequence encoding an activity modulator that is linked to the nucleic acid that encodes for the CAR.
Bedoya et al further disclose that the agent can be an agent which inhibits a molecule that modulates or regulates – or inhibits – T cell function (Paragraph [0562]).
The combination of Bedoya et al, Yang et al, and Ma et al fail to teach that the activity regulator is dominant negative transforming growth factor beta receptor II or dominant negative SHP1 or SHP2, as required by instant claims 2-3.
Jensen et al, however, disclose a system for inducible expression of a chimeric antigen receptor in cells, such as mammalian cells, as well as methods of making such cells (Abstract).
As such, Jensen et al disclose the transduction of the cells with viral vectors, wherein a first viral vector comprises an encoded CAR operably linked to an inducible promoter and further comprises a nucleic acid encoding a modulator of checkpoint signaling and a marker gene, while a second viral vector comprises an encoded transcriptional activator operably linked to a constitutive promoter and further comprises an encoded CAR (Paragraphs [0210], [0213]-[0214], [0228]-[0229], [0231]-[0232], [0256]). Jensen et al further disclose that the modulators of checkpoint signaling include dominant negative transforming growth factor beta receptor II (dn-TGFbetaRII), or dominant negative SHP1 or SHP2 (dn-SHP1/2) (Paragraphs [0210], [0213]-[0214]).
Jensen et al further disclose that the viral vectors can be mixed together for transduction in a cell population (Paragraph [0231]).
Therefore, it would have been prima facie obvious to have modified the method of Bedoya et al in view of Yang et al and Ma et al such that the activity modulator is dn-TGFbetaRII or dn-SHP1/2, as detailed in Jenson et al. One of ordinary skill in the art before the effective filing date of the invention would have been motivated to include dn-TGFbetaRII or dn-SHP1/2 as the activity modulators, as they are genes that inhibit negative checkpoint signaling of the cells (Jensen et al: Paragraphs [0210], [0213]), and would have had a reasonable expectation of success given that the disclosures of Bedoya et al and Jensen et al are concerned with the transduction of cells with vectors to form a reaction mixture. See MPEP § 2143(I)(G).
Consequently, Bedoya et al as modified by Yang et al, Ma et al, and Jensen et al render obvious a method of transducing cells, wherein the activity modulator linked to the CAR is dn-TGFbetaRII (claim 3) or dn-SHP1/2 (claim 2). This therefore renders obvious the method of the instant claims.
Regarding claim 5: As aforementioned in the discussion of claim 1 above, Bedoya et al disclose a viral vector comprising a nucleic acid sequence encoding an activity modulator that is linked to the nucleic acid that encodes for the CAR.
Bedoya et al further disclose that the agent can be an agent which inhibits a molecule that modulates or regulates – or inhibits – T cell function (Paragraph [0562]).
The combination of Bedoya et al, Yang et al, and Ma et al fail to teach that the mixture of viral vectors includes at least one viral vector that encodes an activity regulator is dominant negative transforming growth factor beta receptor II, and at least one viral vector that encodes an activity regulator that is dominant negative SHP1 or SHP2, as required by instant claim 5.
Jensen et al, however, disclose a viral vector comprising an encoded CAR operably linked to an inducible promoter and further comprising a nucleic acid encoding a modulator of checkpoint signaling (Paragraphs [0210], [0213]-[0214], [0228]-[0229], [0231]-[0232], [0256]). With that, Jensen et al disclose that the checkpoint signaling modulators can be either dn-TGFbetaRII or dn-SHP1/2 (Paragraphs [0210], [0213]-[0214]).
Jensen et al further disclose that one or more of vectors can be used in conjunction with one another to transduce target cells and provide for inducible expression of a chimeric antigen receptor (Paragraph [0236]). In addition, Jensen et al further disclose that one, two, or three or more alternatives may be combinable in whole or in part (Paragraph [0348]).
Therefore, it would have been prima facie obvious to have modified the method of Bedoya et al in view of Yang et al and Ma et al such that the viral vector mixture comprises at least one viral vector comprising an encoded CAR operably linked to an inducible promoter and further comprising a nucleic acid encoding dn-TGFbetaRII, and at least one viral vector comprising an encoded CAR operably linked to an inducible promoter and further comprising a nucleic acid encoding dn-SHP1/2. One of ordinary skill in the art before the effective filing date of the invention would have recognized that the viral vector mixture can comprise vectors encoding both checkpoint signaling modulators, as Jensen et al disclose that the alternatives are combinable, and would have had a reasonable expectation of success given that the disclosures of Bedoya et al and Jensen et al are concerned with the transduction of cells with vectors to form a reaction mixture, and Jensen et al reasonably suggest both the encoded checkpoint signaling modulators within embodiments of their invention (Paragraphs [0111], [0210], [0213]-[0214]). See MPEP § 2143(I)(G).
Consequently, Bedoya et al as modified by Yang et al, Ma et al, and Jensen et al render obvious a method of transducing cells with a mixture of viral vectors, wherein at least one viral vector encoding the CAR further comprises a nucleic acid encoding dn-TGFbetaRII and another viral vector encoding the CAR further comprises a nucleic acid encoding dn-SHP1/2. This therefore renders obvious the method of the instant claim.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALYSSA G WESTON whose telephone number is (571)272-0337. The examiner can normally be reached Monday-Thursday 8AM - 4PM (CT); Friday 8AM - 11AM (CT).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Christopher Babic can be reached at (571) 272-8507. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ALYSSA G WESTON/Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633