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 .
DETAILED ACTION
This Action is in response to the papers filed on June 3, 2026. Claims 1-6, 8-15, 17, 19-20, 22, 32 and 75 are currently pending as per claims filed on June 3, 2026. Claims 7, 16, 18, 21, 23-31, 33-74, and 76 have been cancelled in Applicant’s amendment filed on May 21, 2024.
Applicant’s election without traverse of the invention of Group I, e.g., claims 1-6, 8-15, 17, 19-20, drawn to method of preparing genetically modified tumor infiltrating lymphocytes (TILs), in the reply filed on June 3, 2026 in response to the restriction requirement filed on April 3, 2026 is acknowledged.
Claims 22, 32 and 75 are withdrawn from further consideration by the Examiner, pursuant to 37 CFR 1.142(b), as being drawn to non-elected inventions, there being no allowable generic or linking claim. Reinstatement of claims drawn to non-elected inventions will be withdrawn during prosecution. The requirement for restriction between Groups I-IV is maintained for reasons of record, and hereby made FINAL. Applicant timely responded to the Restriction Requirement in the Paper filed on June 3, 2026.
Therefore, claims 1-6, 8-15, 17, 19-20 are currently under examination to which the following grounds of rejection are applicable.
Priority
The present application is a 35 U.S.C. 371 national stage filing of the International Application No. PCT/US22/21356, filed on March 22, 2022. Applicant’s claim for the benefit of a prior-filed parent provisional application 63/165,066 filed on March 23, 2021 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Thus, the earliest possible priority for the instant application is March 23, 2021.
Claim Objections
Claims 4-6 and 13 are objected to because of the following informalities:
Claims 4-6 are objected to for the recitation of “the introducing step” and claim 5 for the recitation of “the expanding step”, as these steps would more properly referred to with a letter before the step, respectively, step (a) and step (b).
Claim 13 is vague in the recitation of “…capable of…”, since this phrase refers to a latent ability, and it is unknown whether the ability is expressed or observed in the invention. Note, it has been held that the recitation that an element is “capable of” performing a function is not a positive limitation, but only requires the ability to so perform.
Appropriate corrections are required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 4 and 19 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 4 contains the trademark/trade name “OKT-3”. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe anti-CD3 mAb and, accordingly, the identification/description is indefinite.
The term “sufficient” in claim 19 is a relative term which renders the claim indefinite. The term “sufficient” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. In particular, there is no diseases or disorder claimed, and therefore it is unclear how a sufficient amount of the expanded TILs is to be determined.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-2, 4, 19, and 20 are rejected under 35 U.S.C. 102(a)(1)(2) as being anticipated by Henley et al. (US 2019/0374576 A1).
Regarding claim 1, Henley teaches preparing genetically modified tumor infiltrating lymphocytes (TILs) comprising reduced expression of CISH (par 0019, 0025), the method comprising: (a) introducing into the TILs nucleic acid(s) encoding one or more first Transcription activator-like effector nucleases (TALE-nuclease) able to selectively inactivate by DNA cleavage a gene encoding CISH (par 0025, 362-363); and (b) expanding the TILs (par 0245). The working examples employ CRISPR to target the CISH gene as seen in Example 10 with gRNA sequences listed in Table 5, 12, yet state TALEN can be used for such engineering.
Regarding claim 2, Henley teaches wherein introducing into the TILs nucleic acid(s) encoding the one or more first TALE-nucleases comprises an electroporation step (par 0019).
Regarding claim 4, Henley teaches prior to step (a), a step of activating TILs by culturing the TILs in a cell culture medium in the presence of OKT-3 (anti-CD3) for about 1-3 days (“Dynabeads Human T-Activator CD3/CD28 beads (Gibco, Life Technologies) were added 3:1 (beads: cells) to the cells… Cells were incubated for 48 hours and then the beads were removed using a dynamagnet.”(par 0537; 0571)).
Regarding claims 19 and 20, Henley teaches wherein the expanded TILs comprise sufficient TILs for administering a therapeutically effective dosage of the TILs to a subject in need thereof, and furthermore the therapeutically effective dosage of the expanded TILs comprises from about 1x109 to about 9x 1010 TILs (par 0509-0513).
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, 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.
Claim 3 is rejected under 35 U.S.C. 103 as being anticipated by Henley et al. (US 2019/0374576 A1) as applied to claims 1-2, 4, 19, and 20, and further in view of Galetto et al. (US 2016/0120906 A1).
Regarding claims 1-2, 4, 19, and 20, the disclosure of Henley is applied as in the 102 rejections above, the content of which is incorporated above, in its entirety.
Regarding claim 3, Henley teaches introducing into the TILs nucleic acid encoding the one or more first TALE-nucleases comprises an electroporation step, but does not explicitly teach the TALE-nucleases delivered in the form of RNA.
Galetto teaches the delivery of TALE-nucleases in the form of RNA via electroporation to primary T cells, wherein the nuclease was successful in downregulation of the target gene with a ~96% editing efficiency (par 0262).
It would have been prima facie obvious for one of ordinary skill in the art at the time of the invention to deliver the TALEN in the form of RNA via electroporation as taught by because it would have been obvious to try such delivery mode as opposed to other options, e.g. viral vector, and in other forms, e.g. DNA plasmid, as the person of ordinary skill would be choosing from a finite number of identified, predictable solutions with a reasonable expectation of success. The option of delivering the TALEN in the form of RNA via electroporation to T cells would have led to a reasonable expectation of success because Galetto teaches that such method is feasible, and more importantly highly successful in gene editing outcomes.
Claims 5-6 are rejected under 35 U.S.C. 103 as being anticipated by Henley et al. (US 2019/0374576 A1) as applied to claims 1-2, 4, 19, and 20, and further in view of Chartier-Courtaud et al. (US 2021/0130779 A1).
Regarding claims 1-2, 4, 19, and 20, the disclosure of Henley is applied as in the 102 rejections above, the content of which is incorporated above, in its entirety.
Regarding claims 5 and 6, Henley teaches using the IL-2 cytokine to facilitate the expansion of lymphocytes and moreover TILs resting for 24 hours after transfection, but does not explicitly teach a rest period for the TILs prior to expansion wherein IL-2 is supplemented for around 24 hours (par 0247, 0570). Additionally, Henley teaches T cells can be frozen, but does not teach thawing and culturing the TILs in a cell culture medium comprising IL-2 for about 1-3 days and then transfected with the TALEN (par 0535).
Chartier-Courtaud teaches a method of expanding gene editing TILs wherein the TILs are rested after electroporation for about 1 day, wherein IL-2 is supplied, and then is followed by an expansion step (par 0345, 0857; Fig. 20, 21). The TILs are frozen prior to expansion steps, which includes the introduction step, then thawed and then cultured accordingly, wherein IL-2 is supplemented at day 0 (par 0288-289, 0627-628, 0643; 0342).
It would have been prima facie obvious for one of ordinary skill in the art at the time of the invention to include a resting step and/or cryopreservation step for the TILs based on these being known and routine steps in the art of cell culturing, and furthermore Chartier-Courtaud teaching these particular steps in view of culturing TILs, and therefore it would be to incorporate these steps in Henley’s method of TIL culturing in which there is a reasonable expectation of success of expanding these cells. In relation to the length or order of these steps, these limitations are considered routine optimization as it would be obvious to determine the length of culturing with IL-2 through routine experimentation.
Claims 8-15, 17 are rejected under 35 U.S.C. 103 as being anticipated by Henley et al. (US 2019/0374576 A1) as applied to claims 1-2, 4, 19, and 20, and further in view of Cabaniols et al. (US 2020/0208174 A1) and Conway et al. (US 2019/0136261 A1).
Regarding claims 1-2, 4, 19, and 20, the disclosure of Henley is applied as in the 102 rejections above, the content of which is incorporated above, in its entirety.
Regarding claims 8-15, 17, the claims are directed to the claimed nuclease, i.e. TALE nuclease, wherein the TALE recited has a first and second half TALE-nuclease, wherein each half is a fusion protein constituted by a TALE binding domain fused to a catalytic domain (claim 9), wherein the binding domains are different between the halves (claim 10), wherein the catalytic domains are the same (claim 11), wherein the catalytic domains are Fok-1 (claim 12), wherein the TALEN is capable of forming a heterodimeric DNA cleavage complex to effect DNA cleavage at the target site in the gene encoding CISH as listed as SEQ ID NO: 175 (claim 13), wherein the target sites in CISH are at different locations that do not overlap (claim 14), TALE nuclease comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 165 and SEQ ID NO: 167 (claim 15), and the first half TALE-nuclease comprising SEQ ID NO: 165 and the second half comprising SEQ ID NO: 167 (claim 17).
Henley teaches the TILs are transfected with TALE nucleases to target the CISH gene for downregulation via knockout (par 0025, 0362); however the structure of the nuclease is not explicitly taught.
Cabaniols teaches the engineering of TILs from a patient (Fig. 6, par 0079), wherein the engineering involves the transfection of a TALE nuclease (0347, 0355). The TALE nuclease structure and function is described as “heterodimeric forms—i.e. working by pairs with a “right” monomer (also referred to as “5′” or “forward”) and ‘left” monomer (also referred to as “3″” or “reverse”)” (par 0110); and “TALE-nucleases are very specific reagents because they need to bind DNA by pairs under obligatory heterodimeric form to obtain dimerization of the cleavage domain Fok-1. Left and right heterodimer members each recognizes a different nucleic sequences of about 14 to 20 bp, together spanning target sequences of 30 to 50 bp overall specificity.” (par 0003).
Cabaniols teaches SEQ ID NO: 5 and 9 that are similar to both instant SEQ ID NO: 165 (97.7%, 97.5%), and SEQ ID NO: 167 (97.2%, 97.3%). The full alignments are provided with the Office Action, for SEQ ID NO: 165 observe Results # 2 and 4, and for SEQ ID NO: 167 observe Results 20 and 25.
Henley in view of Cabaniols do not teach the particular target site in the gene encoding CISH as listed as SEQ ID NO: 175.
Conway et al. teaches as depicted in Figure 1. that shows “partial sequence including exons 2 and 3 (shaded) of a CISH gene (SEQ ID NO:48) and also shows exemplary nuclease target sites (boxed) in the gene.” (par 0048). SEQ ID NO: 48 is 100% identical to instant SEQ ID NO: 175. The full alignment is provided with the Office Action as seen in Result #7.
It would have been prima facie obvious for one of ordinary skill in the art at the time of the invention to state each half of the TALEN as targeting the CISH gene using different binding sites with similar catalytic domains, i.e. Fok-1, based on the structure of TALEN being well-known as operating as heterodimer wherein each unit comprises a Fok-1 nuclease and the binding sites being different as taught by Cabaniols. Additionally, it would then be obvious to use this technology to target the CISH gene based on this gene being well-known in the art, and successfully targeted with nucleases as described by Henley and further supported by Conway wherein the target sequence, SEQ ID NO: 175 is provided therein. By using TALENs to target the CISH gene in TILs there would be a reasonable expectation of success of editing as occurring based on similar work conducted by Henley’s TILs with CRISPR and TALENs for the CISH gene, and furthermore Conway providing additional methods for genomic engineering of the CISH gene using TALENs (par 0017, 0020).
Conclusion
Claims 1-6, 8-15, 17, 19-20 are rejected. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MICHAEL A RIGA whose telephone number is (571)270-0984. The examiner can normally be reached Monday-Friday (8AM-6PM).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maria G Leavitt can be reached at (571) 272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MICHAEL ANGELO RIGA/Examiner, Art Unit 1634
/TERESA E KNIGHT/Primary Examiner, Art Unit 1634
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