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 .
Status of Claims
Claims 1, 4-5, 7, 10-11, 14-17, and 19-33 are pending.
Priority
Claims 1, 4-5, 7, 10-11, 14-17, and 19-33 are a 371 of PCT/US 2022/076165 filed on September 9, 2022, which has priority to PRO 63/242,265 filed on September 9, 2021.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on July 221, 2025, was filed before the mailing of the First Office Action on June 27, 2026. The Non-Patent Literature is in compliance with the provisions of 37 CFR 1.97 and are being considered by the examiner.
Double Patenting
A rejection based on double patenting of the “same invention” type finds its support in the language of 35 U.S.C. 101 which states that “whoever invents or discovers any new and useful process... may obtain a patent therefor...” (Emphasis added). Thus, the term “same invention,” in this context, means an invention drawn to identical subject matter. See Miller v. Eagle Mfg. Co., 151 U.S. 186 (1894); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Ockert, 245 F.2d 467, 114 USPQ 330 (CCPA 1957).
A statutory type (35 U.S.C. 101) double patenting rejection can be overcome by canceling or amending the claims that are directed to the same invention so they are no longer coextensive in scope. The filing of a terminal disclaimer cannot overcome a double patenting rejection based upon 35 U.S.C. 101.
Applicant is advised that should claim 14 be found allowable, claim 19 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m). Both claim 14 and claim 19 recite making a CAR-T cell with reduced TNFR2 expression by CRISPR-mediated disruption of the endogenous TNFR2 gene followed by introduction of chimeric antigen receptor encoding nucleic acid in an ex vivo T cell. The only difference is that claim 14 refers to the nucleic acid sequence to introduced as a construct, while claim 19 refers to the nucleic acid sequence as a complex. However, both result in modified CAR-T cell with disruptive TNFR2 expression. Thus, despite the slight difference in wording, the claims have substantially the same scope.
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.
Claims 1, 4-5, 7, 10-11, 14-17, and 19-33 are rejected under 35 U.S.C. §103 as being unpatentable over Motz et al. [US 2018 258149 A1], in view of Cui et al. [CN 110747211 A, 2020], in view of Schumann et al. [Generation of knock-in primary human T cells using Cas9 ribonucleoproteins, Immunology and Inflammation, 2015].
Regarding claim 1, Motz et al. teaches a method of making a chimeric antigen receptor T cell [Summary of the Invention ¶ 1]. However, Motz et al. does not teach a chimeric antigen receptor T cell having a reduced level of TNFR2. Additionally, Motz et al. discloses a method for engineering T cells to express a chimeric antigen receptor [Para starting with “Accordingly, the present invention provides a cell (e.g., a population of cells…)”]
For this limitation, Cui et al. teaches a method for producing T cells where the TNFR2 gene can be subjected to mutation knockout or fixed-point editing [Background technique ¶ 1] where at least one endogenous allele related to TNFR2 is disrupted leading to a T cell exhibiting reduced levels of TNFR2 and/or inhibiting TNFR2 altogether. Here, it would have been prima facie obvious prior to the filing of the claimed invention to modify the systems and methods of Motz et al. where the authors discuss methods for making improved CAR-T cell therapies with enhanced efficacy with the teachings of Cui et al. where they disclose a method for altering TNFR2 expression in T cells. Given this, there is a reasonable expectation of success that a person of ordinary skill in the art would combine the teachings of both Motz et al. with Cui et al. in order to produce chimeric antigen receptor T cells that either express TNFR2 in a reduced capacity or is inhibited altogether leading to CAR-T cells with reduced expression of TNFR2 where at least one endogenous allele is disrupted.
For claims 4 and 5 where steps (b) and (c) are performed ex vivo, Motz et al. discloses that contacting said T cells occurs ex vivo [Para starting with “In one aspect, the present invention provides a method of increasing the therapeutic efficacy”]. Furthermore, it is well known in the art that conventional CAR-T cell therapy workflow includes collecting T cells from a donor, culturing/activating the T cells outside the body, modifying the T cells, expanding the T cells in culture, and subsequently infusing the T cells back into the donor and/or patient.
Regarding claims 7 and 10, the same analysis found in claim 1 is applied to claim 7 where claim 7 involves a method for making a chimeric antigen receptor T cell [Motz et al. Summary of the invention] that expresses reduced levels of TNFR2 [Cui et al. Background technique] where the T cell possesses an endogenous allele that encodes TNFR2 polypeptide where at least one endogenous allele is further disrupted leading to a reduced expression of TNFR2 leading to a chimeric antigen receptor T cell with reduced expression of the TNFR2.
For claim 11 where the T cells are obtained from a human, Motz et al. teaches that the T cells are obtained from a human [Para starting with “In some embodiments, the immune effector cell of the present invention is a T cell or an NK cell”].
For claim 14 where a method for making chimeric antigen receptor T cells with reduced levels of TNFR2 polypeptide, Motz et al. discloses obtaining T cells ex vivo [Para starting with “In one aspect, the present invention provides a method of increasing the therapeutic efficacy of a CAR-expressing cell]. For the limitations (a) – (c), Cui et al. discloses the use of a guide RNA that is complementary to a messenger RNA encoding TNFR2 [Para starting with “i) a nucleic acid sequence encoding a nuclease system guide RNA”, and SEQ ID NO: 7 (TNFR2 gRNA sequence)], a nucleic acid encoding a Cas nuclease [Para starting with “In recent years, gene editing technology has achieved”]. However, Cui et al. does not teach a nucleic acid encoding a chimeric antigen receptor. For this limitation, Motz et al. teaches a nucleic acid encoding a chimeric antigen receptor [Para starting with “the term “Chimeric Antigen Receptor” or alternatively “CAR”].
Here, it would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the claimed invention to modify the systems and methods of Motz et al. that discloses a method for making and enhancing chimeric antigen receptor T cells that are obtained from a human donor and cultured ex vivo with the additional teachings of Cui et al. that discloses a method for modifying the expression of TNFR2 in T cells. Therefore, there is a reasonable expectation of success that a person of ordinary skill in the art would combine Motz et al. with Cui et al. in order to modify human T cells ex vivo using known genetic engineering tools such as CRISPR to produce chimeric antigen receptor T cells with modified expression levels of TNFR2.
For claim 15 where the guide RNA encoded in a nucleic acid sequence is any one of SEQ ID NOs: 1-6, Cui et al. discloses the identical sequence to Applicant’s SEQ ID NO: 2 in Cui et al.’s SEQ ID NO: 7.
For claims 16 and 17 where the nucleic acid construct is a lentiviral vector, Cui et al. teaches that conventional virus-based systems can include retroviruses, lentiviruses, adenoviruses, adeno-associated viruses, and herpes simplex virus vectors [Para starting with “In some embodiments, conventional virus-based systems”].
Regarding claim 19, the same analysis that is applied to claim 14 is applied here.
For claim 20 where the Cas nuclease is a Cas9 nuclease, both Motz et al. and Cui et al. disclose the use of Cas9 as the Cas system for modifying T cells [Para starting with “the present invention further provides a gene editing system” and Para starting with “In recent years, gene editing technology has achieved”, respectively].
For claim 21 where the said complex of claim 19 is a ribonucleoprotein, Schumann et al. teaches the use of Cas9 ribonucleoproteins as a viable means for enabling successful Cas9 mediated homology-directed repair in primary human T cells and is allows for the ability to replace specific nucleotide sequences in the genome of mature immune cells [Significance ¶ 1].
For claim 22 where the introduction steps utilize electroporation, Schumann et al. further discloses the use of electroporation where it was shown that electroporation of Cas9 ribonucleoproteins lead to efficient genome editing [Main body ¶ 3]. Therefore, there is a reasonable expectation of success that a person of ordinary skill in the art would recognize that electroporation would be a viable means for introducing efficient gene editing in T cells when using Cas9 ribonucleoproteins. Furthermore, it would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the claimed invention to modify the systems and methods of Motz et al. that discloses a method for making enhanced chimeric antigen receptor T cells and Cui et al. where the authors disclosed a means for reducing and/or inhibiting TNFR2 in T cells with the methods of Schumann et al. where the authors discloses the use of electroporation in conjunction with Cas9 ribonucleoprotein as the selected means for editing T cells.
For claim 23 that relates to a T cell that contains a disruption of at least one endogenous allele encoding TNFR2 and encodes a chimeric antigen receptor, the same analysis for claims 1, 7, and 10 are applied here.
For claim 24 where the T cell is obtained from a human, Motz et al. teaches that the T cells or NK cells are obtained from a human [Para starting with “In some embodiments, the immune effector cell of the present invention”].
For claim 25 where the T cells comprise disruption in both endogenous alleles, Cui et al. teaches that the specific genes, including TNFR2, can be subjected to mutation knockout or fixed-point editing, i.e. disrupting both endogenous alleles [Para starting with “In recent years, gene editing technology has achieved”].
For claims 26 and 27 where the chimeric antigen receptor targets a tumor-associated antigen CD19, Motz et al. teaches the antigen binding domain binds to a tumor antigen that is selected from a group that includes CD19, as well as other known tumor antigens [Para starting with “Accordingly, the present invention provides a cell (e.g., a population of cells…)”].
For claim 28 where modified T cells having improved antitumor activity vs T cell lacking said disruption, Motz et al. teaches making chimeric antigen receptor T cells while Cui et al. teaches a method for decreasing/disrupting the expression of TNFR2 in T cells. Although neither reference expressly states that antitumor activity is improved over CAR-T cells that don’t exhibit a reduction in TNFR2, it would have been prima facie obvious to modify the CAR-T cells of Motz et al. with the TNFR2 disruption techniques taught by Cui et al where T cells were modified to inhibit or reduce the expression of TNFR2. Applicant’s asserted improvement of antitumor activity is attributable to the reduction in TNFR2 expression. Given this, the combined references of Motz et al. and Cui et al. teach the same CAR-T cells that have a reduced and/or inhibited expression of TNFR2. Therefore, the enhanced antitumor activity resulting from reduced and/or inhibited TNFR2 expression in T cells would have been an inherent property of the combined teachings of Motz et al. and Cui et al.
For claim 29 where the method involves treating a mammal with the composition comprising the CAR-T cells with reduced TNFR2 expression, Cui et al. discloses administering modified T cells to a subject in need in a therapeutically effective amount [Para starting with “b) administering a therapeutically effective amount”]. Although Cui et al. does not specifically reference chimeric antigen receptor T cells combined with Cui et al. with the teachings of Motz et al. where the authors disclose making enhanced CAR-T cells, there would be a reasonable expectation of success that a person of ordinary skill could combine the teachings of both Motz et al. and Cui et al. in order for modified CAR-T cells that have reduced expression of TNFR2 would be able to administer said composition to a subject in need.
For claim 30 where the composition comprises a concentration range, selection of a particular dose, concentration, or number of administered modified CAR-T cells would be recognized by a person of ordinary skill in the art as routine optimization. A person of ordinary skill would have known to adjust the administered concentration or cell dose using standard dosing escalation in order to obtain a therapeutic response and would have been within the ordinary skill in the art.
For claim 31 where the mammal has cancer, Motz et al. teaches administering a modified T cell composition to a subject [Para starting with “In one aspect, the present invention provides a method for treating a subject in need thereof”].
For claim 32 where the mammal is a human, Motz et al. discloses that the term “subject” is intended to include living organisms that include both mammals and humans [Para starting with “The term “subject” is intended”].
For claim 33 where the cancer is lymphoma, Motz et al. discloses that multiple cancers, including various types of lymphomas are currently treated with CAR expressing cell therapy [Para starting with “In one aspects, the present invention provides a method for treating a subject in need thereof”].
Here, it would have been prima facie obvious to person of ordinary skill in the art prior to the filing of the claimed invention to modify the systems and methods of Motz et al. where chimeric antigen T cells were further modified for improved efficacy with the additional teachings of both Cui et al. that discloses a method for disrupting and/or inhibiting the expression of endogenous alleles associated with TNFR2 and the teachings of Schumann et al. that further disclosed the use of Cas9 ribonucleoproteins as a means for modifying genes in T cells to develop a modified CAR-T cell that exhibits disrupted TNFR2 expression either partially or completely that can then be combined with a pharmaceutical acceptable carrier for administering to a human subject, i.e. mammal, in need for the purpose of treating lymphoma-type cancers. Given this, there is a reasonable expectation of success that a person of ordinary skill would be able to combine the teachings of Motz et la. with Cui et al. and Shumann et al. for the purpose of developing modified CAR-T cells with reduced expression of TNFR2 that can then be used as a therapeutic treatment for lymphoma-type cancers in human subjects.
The Supreme court has acknowledged:
When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one. If a person of ordinary skill can implement a predictable varition..103 likely bars its patentability…if a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond that person’s skill. A court must ask whether the improvement is more than the predictable use of prior-art elements according to their established functions…
…the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results (see KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 U.S. 2007) emphasis added.
In KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court reaffirmed "the conclusion that when a patent 'simply arranges old elements with each performing the same function it had been known to perform' and yields no more than one would expect from such an arrangement, the combination is obvious." Id. at 417 (quoting Sakraida v. Ag Pro, Inc., 425 U.S. 273,282 (1976)). The Supreme Court also emphasized a flexible approach to the obviousness question, stating that the analysis under 35 U.S.C. § 103 "need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418; see also id. at 421 ("A person of ordinary skill is... a person of ordinary creativity, not an automaton.").
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
No claims allowed.
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/JOHN DAVID MOORE/Examiner, Art Unit 1638
/Tracy Vivlemore/ Supervisory Primary Examiner, Art Unit 1638
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