tteNotice 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 .
Request for Continued Examination
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 July 20th 2026 has been entered.
DETAILED ACTION
Status of the Claims
Claims 1-21 are pending. Claims 10-21 are withdrawn from further consideration as being directed towards nonelected species until a generic claim has been found allowable. Claims 1-9 are examined on their merits.
35 U.S.C. § 102 Rejections Overcome by Amendment
Applicant’s amendments to claim 1 in the response filed on July 20th 2026 are acknowledged. Applicant has amended claim 1 to recite that the method ‘selectively enhances cell surface persistence of an antigen in the target cells for 7 days or more.” As this time period is not explicitly disclosed in the methods described by either Biberacher or Liu, all 102 rejections are withdrawn.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 3-5 are rejected 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. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 3 and its dependent claims are rejected under 35 U.S.C. §112(a) for reciting a method that is not described by the specification.
Disclosed Working Examples
Applicants describe a method of modulating target cells (for example, cancer cells or HIV infected cells) via application of a bryostatin agent. Such application of the bryostatin agent would increase expression of cell surface antigens, such as CD22. Such antigens are more easily recognized by T cells (for example, lab-modified CAR-T cells), improving immunotherapeutic outcomes by allowing for the T cells to persist on the surface of the infected/cancerous cells longer.
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As described by the specification:
“The subject methods can be used in combination with chimeric antigen receptor-T cell therapy (CAR-T cell therapy) and chimeric antigen receptor-natural killer cell therapy (CAR-NK) to improve patient response and prevent patient relapse driven by low and variable surface expression of an antigen on target cells of interest. Treatment with CAR-T cell therapy has, in part, been limited by diminished and variable target antigen expression, the induction of antigen-specific toxicities targeting normal tissues expressing the target-antigen, and the extreme potency of CAR-T cell and/or CAR-NK cell treatments resulting in life-threatening cytokine-release syndromes. In particular, it has been observed that high affinity T cell receptor interactions with significant antigen burden can lead to activation-induced cell death.”
[Specification, Paragraph [0147]]
“Bryostatin 1, a marine macrolide, can alter expression of surface antigens in tumor and other cell lines, making them more immunogenic and thus more susceptible to immune clearance. The data presented herein indicates that a bryostatin agent may be used in conjunction with CAR-T cell therapy to enhance the activity of CAR T cells by increasing the number and density of cell surface antigens on target cells.”
[Specification, Paragraph [0149]]
“A particular embodiment contemplates a method of modulating a T cell-mediated or NK cell-mediated immune response to a target cell population in a subject, comprising a) introducing to the subject a therapeutically effective plurality of cells genetically modified to express a chimeric antigen receptor, wherein the chimeric antigen receptor comprises at least one antigen-specific targeting region capable of binding to the target cell population, and wherein the binding of the chimeric antigen receptor targeting region to the target cell population is capable of eliciting activation-induced cell death; and b) administering to the subject a therapeutically effective amount of a bryostatin agent sufficient to prevent or limit the activation-induced cell death. In particular embodiments, the CAR comprises an antigen binding domain which specifically recognizes a CD22 target cell population. In certain embodiments of the present disclosure, the bryostatin agent enhances the function of activated memory CD8+ T cells. In other embodiments, the amount of the bryostatin agent administered is sufficient to enhance cytotoxic function. In certain cases, the amount of bryostatin agent administered is sufficient to enhance the activity of CAR T cells by increasing the number of cell surface antigens on target cells.”
[Specification, Paragraph [0301]]
The Invention of Claims 3-5
Claim 3 and its dependent claims recite “the method of claim 1 wherein the target cells are CAR-modified T cells or CAR-NK cells and the contacting target cells with the bryostatin agent enhances expression or cell surface presentation and persistence of the CAR.”
Claim 3 is thus limiting the target cells receiving the bryostatin agent to be the CAR-T cells, and further requiring that the enhancement of cell surface presentation and persistence of CAR cells. That is, the claim limits the method of modulating target cells of claim 1 to require that the target cells being modulated, and receiving “enhancement of cell surface persistence of an antigen” are either CAR-T or CAR-NK cells:
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The Invention of Claims 3-5 is Not Supported by the Specification
As described by the specification, the target cells and the CAR-T/CAR-NK are distinct entities. The method disclosed by applicant describes the administration of the bryostatin agent to cells in order to enhance cell surface persistence of an antigen that would further be recognized by the CAR-T/CAR-NK cells, but nowhere is the treatment wherein the target cells are CAR cells disclosed.
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Claims 3-5 Fail to Comply with the Written Description Requirement
One of ordinary skill in the art would reasonably understand that the inventors possessed methods of modulating antigen density on the surface of target cells in order to improve immunotherapy (including the efficacy of CAR-T therapy).
The specification does not reasonably convey possession of the method recited in claim 3, wherein the CAR-modified effector cells are the “target cells” and the bryostatin agent acts to enhance CAR itself on said cells.
Applicant is thereby not considered to be in possession of claims 3-5 as written.
Either appropriate amendments to restore consistency of claims 3-5 with the specification, or evidence that the specification supports the CAR-as-target embodiment is required.
35 U.S.C. § 103 Rejections Necessitated by Amendment
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.
Claims 1-2 and 6-9 are rejected under 35 U.S.C. 103 as being unpatentable over Biberacher (Biberacher et al., The cytotoxicity of anti-CD22 immunotoxin is enhanced by bryostatin 1 in B-cell lymphomas through CD22 upregulation and PKC-βII depletion. Haematologica. 2012 May;97(5):771-9).
Claim 1 is directed towards the modulation of cells in a subject via administration of a bryostatin agent to selectively enhance surface persistence of an antigen in the target cells for 7 days or more.
Biberacher teaches that bryostatin 1 enhances surface expression of CD22 on chronic lymphocytic leukemia cells (Biberacher, abstract, results). Biberacher further describes the upregulation of CD22 for several days following pre-stimulation with bryostatin 1 (Biberacher, abstract, results). That is, Biberacher demonstrates that an increase in the persistence of cell surface antigens occurs after contact with bryostatin 1.
Regarding the particular time period of said enhanced surface persistence, Biberacher does not explicitly demonstrate that the persistence of cell surface antigens for a period of 7 days or more. However, Biberacher does treat such cell surface antigen persistence as a result-effective variable:
“Depletion of protein kinase C-βII and upregulation of CD22 persist for several days following pre-stimulation with bryostatin 1. Therefore, our data provide a rationale for the sequential administration of BL22 following bryostatin 1 treatment.”
[Biberacher, abstract, results]
“Furthermore, we demonstrate in vitro that the combination of bryostatin 1 and BL22 can be separated temporally, allowing enhanced cytotoxicity and potentially decreasing side effects in vivo.”
[Biberacher, introduction]
Biberacher is stating that, by increasing the length of time in which CD22 is upregulated (i.e. increasing the length of which the cell surface antigens persist), the targeted immunotoxin, BL22, can be given at a later point in time, thus allowing for decreased side effects than what would have been present had the bryostatin 1 and BL22 been administered closer together. One of ordinary skill in the art would therefore have a reasonable expectation of success in optimizing the time period of the cell surface antigen persistence. See MPEP 2144.05(II)(A):
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.).
In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929) ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416, 82 USPQ2d 1385, 1395 (2007) (identifying "the need for caution in granting a patent based on the combination of elements found in the prior art.").
As the optimization of the cell surface antigen persistence to a period of time greater than 7 days is obvious, claim 1 is prima facie obvious.
Claim 2 limits the antigen of claim 1 to a protein antigen. Biberacher bryostatin for the enhanced expression of CD22, and claim 2 is thereby prima facie obvious.
Claim 6 requires that the target cells of claim 1 are cancer cells. As Biberacher teaches chronic lymphocytic leukemia cells, claim 6 is prima facie obvious.
Claim 7 requires that the method of claim 6 occurs in vivo. Biberacher suggests an in vivo contacting step (Biberacher, pg. 778, col. 2), and claim 7 is thereby prima facie obvious.
Claim 8 requires that, in the method of claim 6, the method sensitizes the target cells to clearance by the subject’s immune system. Biberacher teaches that bryostatin 1 sensitizes chronic lymphocytic leukemia cells to the cytotoxic effects of BL22, a human immunotoxin (Biberacher, abstract, results). Claim 8 is thereby prima facie obvious.
Claim 9 requires that, in the method of claim 7, a second agent capable of inhibiting growth of the modulated target cells or clearing out the modulated target cells is administered. Biberacher suggests a combination of bryostatin 1 with antibodies directed against CD22 as a drug combination for the treatment of B-cell lymphoma (Biberacher, abstract, conclusions). Claim 9 is thereby prima facie obvious.
Relevant Art
The specification describes the administration of the bryostatin agent to cells in order to enhance cell surface persistence of an antigen that would further be recognized by the CAR-T/CAR-NK cells. Fry and Ramakrishna are attached as relevant art for this particular embodiment (Fry et al., CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy. Nat Med. 2018 Jan;24(1):20-28) (Ramakrishna et al., Modulation of CD22 Antigen Density Improves Efficacy of CD22 Chimeric Antigen Receptor (CAR) T Cells Against CD22lo B-Lineage Leukemia and Lymphoma, Blood, Volume 130, Supplement 1, 2017, Page 3894).
Nonstatutory Double Patenting Rejections
Response to Arguments
Applicant has requested that the nonstatutory double patenting rejections over claims 1-2 and 6-9 be held in abeyance until the above 102 rejections over claims 1-2 and 6-9 have been overcome. The nonstatutory double patenting rejections are thereby maintained.
Nonstatutory Double Patenting Rejections
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-2 and 6-9 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of U.S. Patent No.12,435,071. Although the claims at issue are not identical, they are not patentably distinct from each other because the reference patent teaches the administration of a bryostatin agent to subjects with cancer. The results of such administration would necessarily be the modulation of the cancer cells (regardless of whether or not such modulation was intended).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Anthony Seitz whose telephone number is (703)756-4657. The examiner can normally be reached 7:30 AM ET - 5:00 PM ET M-F.
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/ANTHONY JOSEPH SEITZ/Examiner, Art Unit 1629
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