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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 02/19/2026 has been entered.
Claims Status
No amendments were made and all claims appear as previously presented. Claim 12 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 09/19/2024.
Claims 1-11 and 15-21 are pending and are examined on the merits.
REJECTIONS MAINTAINED
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:
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.
Claims 1-11, 15-16 and 19-21 remain rejected under 35 U.S.C. 103 as being unpatentable over Allison and Curran 2011 (US 2011/0044953 A1; of record), herein “Allison”, in view of Pegram et al. 2012 (Blood, 119(18), 4133-4141.; of record), herein “Pegram”.
Regarding instant Claims 1-2, 4-5, and 11, Allison teaches a T cell (i.e. an “immunoresponsive cell”) comprising an anti-CTLA-4 blocking antibody (Allison claims 12-14; ¶0055; ¶0116; Pg. 5 § “CTLA-4 Antibodies”), wherein said antibody comprises an scFv (Allison claim 4; Pg. 6, ¶0095; Fig. 4) which is secreted (Pg. 7, ¶0095). Allison further teaches that CTLA-4 is a polypeptide that has immunosuppressive activity (¶0003), and that tumor-specific T cells expressing anti-CTLA-4 “may protect themselves and other endogenous and/or adoptively transferred tumor-specific T-cells from being silenced” by the suppressive tumor environment (¶0055). Moreover, Allison teaches that methods of producing scFv antibody fragments are known in the art (¶0086; ¶0095), and antibodies lacking an Fc region provide advantages owing to their lack of effector function (¶0088; ¶0091).
Regarding the requirement that the scFv is “soluble”, as recited in instant Claim 1, Allison teaches that, when expressed in vitro, the anti-CTLA4 scFv is secreted and can be collected from the supernatant (¶0129-0131, “Example 3”), satisfying the definition of “soluble” according to Pg. 29 of the instant specification (“freely diffusible in an aqueous environment (e.g. not membrane bound)”).
Regarding instant Claims 7-8, Allison teaches that the T cells comprising anti-CTLA-4 antibodies can be adoptively transferred T cells “specific for particular tumor antigens” (¶0055), which one of ordinary skill in the art would readily conclude are T cells comprising “an antigen recognizing receptor” wherein “the antigen is a tumor antigen”.
Regarding instant Claim 3, Allison teaches that the scFv is encoded by a viral vector which provides constitutive expression when incorporated into human cells (¶0007; Pg. 5, § “Anti-CTLA-4 Viral Vectors”; Allison claims 1 and 7), and that additional components may be expressed from the same vector, such as cytokines (¶0008; Allison claim 2).
Regarding instant Claims 19-20, Allison teaches that the cells “can be combined with a pharmaceutically acceptable carrier to form a pharmaceutical composition” (¶0098), which can be provided as a kit comprising, for example, “a composition comprising a cell…together with a means for administering the cell” (¶0113).
In addition, Allison teaches that the cells comprising anti-CTLA-4 scFv deliver localized secretion of a blocking antibody proximal to a tumor cell or mass and that localized expression is useful to reduce or inhibit undesired adverse immune responses (¶0083). Moreover, Allison teaches that the antibody-secreting cells may be combined with other treatments that augment the immune response, including administration of IL-12 (¶0062), and further suggests that local expression of cytokines in proximity to tumor cells, as with localized antibody expression, releases responding T cells from inhibitory signals (¶0084).
Allison does not teach that the T cell is a cytotoxic T cell (Claim 6), that the tumor antigen is CD19 (i.e. a “blood cancer antigen”; Claims 9-10 and 21), nor that the antigen recognizing receptor is a CAR (all Claims). These deficiencies are cured by Pegram.
Pegram teaches T cells comprising a CD19-specific CAR and further modified to constitutively express IL-12 (Abstract), wherein both the CD19 CAR and secreted IL-12 are expressed from the same viral vector using an IRES element (Fig. 3). Pegram further teaches the CD19 antigen is specific to B cell populations and is present on various cancers, but is absent from stem cells and bone marrow - suggesting CD19 is a relatively safe target for adoptive T cell therapies (Introduction). Pegram teaches that T cells expressing both a CD19 CAR and IL-12 can been used to eradicate CD19+ tumors (Fig. 3), obviating the need for pre-conditioning patients with immune modulating drugs (Abstract; Discussion).
Pegram teaches that IL-12 secreting tumor-targeted T cells are resistant to Treg-mediated immunosuppression (Abstract, Fig. 4), and that targeted T cells would ideally deliver IL-12 directly to the tumor site, thereby avoiding significant toxicities previously observed with systemic infusion of IL-12. Consistent with this, treatment with IL-12–secreting CAR T cells was well tolerated with no toxicities noted in treated mice (§ Discussion, Pg. 4140, ¶4).
Regarding Claim 6, Pegram teaches that the T cells comprising anti-CD19 CAR (“19mz+” and “19mz/IL-12+”) possessed cytotoxic activity (Fig. 1B-C; Fig. 4) and that a significant fraction of the transduced T cells were CD8+ (Fig. 4).
Regarding Claims 15-16, Pegram teaches a CAR comprising an extracellular CD19 scFv, a CD8 transmembrane domain, and an intracellular CD3ζ signaling domain (§ Methods, “Generation of retroviral constructs”; Fig. 1A, 3A).
One of ordinary skill in the art would have recognized the functional similarity between the anti-CTLA-4 blocking scFv taught by Allison and the exogenous IL-12 taught by Pegram (i.e. protecting T cells from the immunosuppressive tumor microenvironment) because Allison teaches that both cytokines and antibodies targeting immunosuppressive proteins can similarly release T cells from inhibitory signals when expressed in proximity to tumor cells (¶0084). In addition, both Allison (¶0083) and Pegram (§ Discussion, Pg. 4140, ¶4) teach that using the adoptive cells as a delivery mechanism for secreted immune-modulating peptides restricts expression proximal to the tumor site, thereby avoiding potential toxicities or adverse reactions associated with systemic administration of exogenous cytokines or blocking antibodies.
Accordingly, it would have been obvious to modify the T cells secreting anti-CTLA4 scFv as taught by Allison to include the CD19 CAR taught by Pegram. It would have been obvious to the skilled artisan that this could be accomplished by substituting the IL-12 in the CD19-CAR construct taught by Pegram with the scFv taught by Allison, resulting in a T cell expressing both a CD19-CAR and a secreted scFv specific for CTLA-4.
The skilled artisan would have been motivated to combine the teachings of Allison and Pegram to make a T cell comprising a secreted anti-CTLA-4 scFv and an anti-CD19 CAR because Pegram teaches that T cells co-expressing a CAR and an immunomodulatory agent obviates the need for preconditioning patients, and Allison teaches that localized delivery of blocking scFv proximal to tumor cells can decrease adverse immune responses.
There would have been a reasonable expectation of success because 1) Allison teaches that viral vectors can be used to express scFvs from T cells, 2) Allison suggests that additional components can be expressed alongside the scFv and Pegram teaches that a secreted polypeptide can be expressed from the same viral vector as the CD19 CAR by use of an IRES element, and 3) both Allison and Pegram teach that the addition of an immunomodulatory peptide – whether it be exogenous cytokines (Allison and Pegram) or blocking antibodies against immunosuppressive signals (Allison) – have the potential to augment adoptive T cell therapies.
Claims 17-18 are rejected under 35 U.S.C. 103 as being unpatentable over Allison and Curran, 2011 (US 2011/0044953 A1; of record), herein “Allison”, Pegram et al. 2012 (Blood, 119(18), 4133-4141.; of record), herein “Pegram”, as applied to claims 1 and 15 above, and further in view of Milone et al. 2009 (Molecular therapy, 17(8), 1453-1464.; of record), herein “Milone”.
The teachings of Allison and Pegram are summarized above.
Allison and Pegram do not teach an anti-CD19 CAR further comprising a 4-1BB or CD28 intracellular signaling domain. This deficiency is cured by Milone.
Milone teaches anti-CD19 CARs comprising an intracellular ζ chain signal transduction domain in tandem with a CD28 and/or 4-1BB intracellular domain(s) (Abstract; Fig. 1). Milone teaches that both CD28 and 4-1BB domains enhance CAR T cell proliferation (Fig. 4), and that CARs comprising the 4-1BB costimulatory domain display enhanced CAR T cell survival and improved antileukemic efficacy (Fig. 6-7).
It would have been obvious to one of ordinary skill in the art to further modify the anti-CD19 CAR taught by Pegram to include a 4-1BB costimulatory domain in tandem with the CD3ζ, resulting in a T cell comprising a secreted anti-CTLA-4 scFv and an anti-CD19 CAR, as taught by Allison and Pegram, wherein the CAR comprises an extracellular CD19 scFv, a CD8 transmembrane domain, and both a 4-1BB and a CD3ζ signaling domain. The skilled artisan would have been motivated to include a 4-1BB costimulatory domain to improve the efficacy of the anti-CD19 CAR in treating leukemia. There would have been a reasonable expectation of success because Milone teaches that anti-CD19 CAR-T cells comprising a 4-1BB intracellular domain display greater proliferation and enhanced survival in a leukemia model.
Claims 1-11, 15-16, and 19-21 are rejected under 35 U.S.C. 103 as being unpatentable over Allison and Curran, 2011 (US 2011/0044953 A1; of record), herein “Allison”, and Pegram et al. 2012 (Blood, 119(18), 4133-4141.; of record), herein “Pegram”, as applied to claims 1-10, 15-16, and 19-21 above, and further in view of Darcy et al. 2012 (International Journal of Molecular Medicine. Vol. 30. pS44; of record), herein “Darcy”, and Korman (WO 2006/121168 A1; of record).
The teachings of Allison and Pegram are summarized above.
Allison and Pegram do not teach that the secreted scFv is specific for PD-1 (Applicant’s elected species). This deficiency is cured by Darcy and Korman.
Darcy teaches that immunosuppression by PD-L1+ tumor cells “can restrict the full potential of adoptive T cell therapy” and that administration of anti-PD-1 blocking antibodies “can potently enhance CAR T cell therapy”, resulting in greater inhibition of tumor growth and higher numbers of transduced T cells within the tumor microenvironment (Abstract).
Korman teaches an anti-PD-1 scFv (Korman claim 4, “single chain antibody”; Pg. 18 ¶1). Korman teaches that PD-1 is an inhibitory member of the CD28 family that also includes CTLA-4 (Pg. 1, ¶2), and immune suppression of T cells can be reversed by inhibiting interaction of PD-1 with its ligands (Pg. 2, ¶1). Korman further teaches that blocking either CTLA-4 or PD-1 has a similar impact on tumor growth (Fig. 21B-C), and that anti-PD-1 alone or a combination of anti-PD-1 with anti-CTLA-4 produce a persistent immunity to tumor relapse (Fig. 49; Pg.97 ¶1).
It would have been obvious to substitute the anti-CTLA-4 scFv in a T Cell expressing both a CD19 CAR and anti-CTLA-4 scFv as taught by Allison and Pegram with the anti-PD-1 scFv taught by Korman because Korman teaches blocking either PD-1 or CTLA-4 improves cancer response and Darcy teaches that a PD-1 blockade improves CAR-T therapy.
The skilled artisan would have been motivated to do so in order to improve CAR-T therapy in patients with B-cell malignancies because Darcy teaches that adding PD-1 blocking antibodies result in greater inhibition of tumor growth than CAR-T alone, Allison teaches that scFvs are advantageous over full length antibodies due to their lack of effector function, and Allison teaches localized delivery of blocking scFv proximal to tumor cells can decrease adverse immune responses.
There would have been a reasonable expectation of success because Allison teaches that methods of making scFvs from antibodies are known in the art, Pegram teaches that CD19 is an effective and relatively safe target for B cells, Korman teaches that PD-1 and CTLA-4 blockades are both effective and limiting tumor growth, and Darcy teaches the addition of PD-1 blockade to CAR-T therapy results in a higher number of transduced T cells within the tumor microenvironment.
Response to Arguments
Applicant's arguments filed 02/19/2026 have been fully considered but they are not persuasive because:
Because no amendments were made to the claims in the response filed 02/19/2026, the rejections above are maintained as previously presented. Each of Applicant’s arguments relate generally to the contention that the state of the art and teachings of the primary reference Allison comprise “substantial unpredictability in the field that undermines any reasonable expectation of success” in making the claimed invention. Each argument is responded to in order below:
First, Applicant states that “Allison reported that only the “B16-GM0CSF 909 [sic] cells showed reduced tumor size and increased CD8+ proliferation.” See Allison at [0143].” (Remarks, Pg. 6, ¶2; emphasis added). However, this is a mischaracterization of the teachings of Allison. While ¶0143 does indeed highlight that particular result, Allison does not suggest that this was the “only” condition that resulted in reduced tumor size. As can be seen in Fig. 11 (copied below), the B16-GMCSF+9D9 and B-16GMCSF-9D9scFv-Ig cells, both with and without the addition of the PC-61 antibody, resulted in reduced tumor size relative to B16-GMCSF alone.
PNG
media_image1.png
877
1242
media_image1.png
Greyscale
In addition, Applicant states that “According to the Examiner’s position, a person of ordinary skill in the art would have expected that depleting T-reg cells (i.e., by administering PC-61) would uniformly increase the CD8+/FoxP3+ ratio.” (Remarks, Pg. 6, ¶2). However, as is clear from the prosecution history, Examiner has not taken any position on the influence of PC61 in combination with localized anti-CTLA-4 over the CD8+/FoxP3+ ratio, and the topic has not been previously argued or discussed. It is further unclear what relevance the results of systemic administration of anti-CD25 antibody PC61 have to the motivation and/or reasonable expectation of success regarding the instantly claimed invention of an immune cell expressing a combination of a CAR and locally secreted scFv.
Nevertheless, to the extent that Applicant argues that the results in said experiment were “inconsistent”, it is noted that the results of Allison are not as described by Applicant (See Remarks, Pg. 6, ¶2: “while the B16-GM+9D9/PC61 condition exhibited an increased ratio compared to its control, the B16-GM-9D9Ig/PC61 condition showed a decreased ratio”). In contrast to Applicant’s statements, and as can be clearly seen in Fig. 12 (copied below; relevant data points highlighted), the B16-GM+9D9 and B16-GM-9D9Ig conditions, with and without PC61, exhibited nearly identical patterns – with all four conditions having a greater CD8+/FoxP3+ ratio than B16-GMCSF alone, and the addition of PC61 to either the B16-GM+9D9 or B16-GM-9D9Ig exhibiting a slight decrease in CD8+/FoxP3+ ratio relative to the same condition without the added PC61.
PNG
media_image2.png
657
579
media_image2.png
Greyscale
Next, Applicant turns to Kerkar and Resifo 2012 (Blood, 119(18), 4096-4097.; of record) to highlight the general unpredictability of the CAR T field. However, Applicant does not point to any particular results or statements in Kerkar that speak to directly to this point. Moreover, Applicant is reminded that absolute predictability not a requirement for an obviousness determination, and existing working examples of CAR T therapies – such as the CD19 CAR highlighted by Kerkar – would have provided the skilled artisan with a reasonable expectation of success.
Finally, Applicant contends that the data presented in Allison is insufficient to “establish that the reference teaches or even suggests that a desired immunostimulatory effect would reliably occur” owing to disparate results reported for tagged and untagged versions of the anti-CTLA4 scFv (Remarks, Pg. 7, ¶1).
In response, Examiner again points out that Allison demonstrates working examples of anti-CTLA-4 scFv-secreting immune cells having the desired immunostimulatory activity, which alone would provide the skilled artisan with a reasonable expectation of success. Only the examples comprising a Myc and/or HIS tag attached to the anti-CTLA4 exerted an opposite, immunosuppressive effect – which Allison attributes to the peptide tag itself. Applicant argues that this hypothesis of Allison is not “scientifically sound” because “protein tags have been used for decades in the scientific literature at least in part due to their ability to non-interfere with the biological function of the polypeptide to which they are attached” (Remarks, Pg. 7, ¶1).
On the contrary, however, at the time of filing it was well understood in the art that even small peptide tags could interfere with protein function or generate unwanted immunogenicity. For example, Khan et al. 2012 (Biotechnology journal, 7(1), 133-147.; PTO-892) teaches that the common HIS tag impacts a number of different properties of the tagged protein and states that “[a]lthough generally viewed as supportive of product development, affinity tags may have unintended consequences on protein solubility, susceptibility to aggregation, and immunogenicity” (Abstract). Khan concludes that “the usefulness of protein tags may be outweighed by their potential impact on structure and function, stressing the need for caution in their use” (Abstract). Accordingly, the skilled artisan would have understood that peptide affinity tags have the capacity to dramatically alter protein function, and the teachings of Allison would have motivated the skilled artisan to forgo foreign peptide tags on the anti-CTLA4 scFv – not to avoid its implementation altogether.
Conclusion
No claim is allowed.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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 nonprovisional extension fee (37 CFR 1.17(a)) 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 mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRYAN WILLIAM HECK whose telephone number is (703)756-4701. The examiner can normally be reached Mon-Fri 8:00am - 5:30pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Wu can be reached at (571) 272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/BRYAN WILLIAM HECK/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
Prosecution Insights