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 .
Status of Claims
Claims 1, 3-11, and 14-23 are pending and examined on the merits herein.
Claims 2 and 12-13 are cancelled.
Priority
The instant application is a 371 of PCT/US2022/079843 filed 11/14/2022, which claims benefit of US Provisional Application 63/278,447 filed 11/11/2021.
Claim Objections
Claims 1, 3, and 20 are objected to because of the following informalities:
Claim 1 recites the embodiment (ii) twice in line 3. The second occurrence of (ii) should be corrected to (iii).
Claim 3 recites the limitation “reference TILs,” which should be written out as “corresponding TILs that have not been modified.”
Claim 20 recites the phrase “in the absence of exogenous cytokine” in lines 2-3, which should be corrected to “in the absence of an exogenous cytokine”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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 1, 3-11, and 14-23 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.
Claims 1 and 20 recite the phrase “corresponding TILs that have not been modified (reference TILs)” in the last two lines. It is not clear if what is encompassed in parentheses is actually claimed or is exemplary. To overcome the rejection, the parenthetical phrase “(reference TILs)” should be deleted from the claims. Claims 3-11, 14-19, and 21-23 are included in the rejection because they depend from claim 1 or claim 20.
The term “at least about” in claims 3-4 is a relative term which renders the claims indefinite. The term “at least about” is indefinite because the limitation “at least” sets a lower limit, and the limitation “about” removes said limit. Therefore, the metes and bounds of the numerical range encompassed by the limitation “at least about” is unclear.
Claim 9 recites the phrase “wherein after the nucleic acid encoding the co-stimulatory molecule and/or the nucleic acid encoding the cytokine, the input TILs exhibit increased expression of the co-stimulatory molecule and/or cytokine to become the TILs that have been modified” (lines 5-8). The object of the phrase “the nucleic acid encoding the co-stimulatory molecule and/or the nucleic acid encoding the cytokine” is missing, and therefore, it is unclear what step is being referred to by the phrase “wherein after the nucleic acid encoding the co-stimulatory molecule and/or the nucleic acid encoding the cytokine.” For the purpose of examination, lines 5-8 of claim 9 is interpreted as “wherein after the nucleic acid encoding the co-stimulatory molecule and/or the nucleic acid encoding the cytokine entered the input TILs, the input TILs exhibit increased expression of the co-stimulatory molecule and/or cytokine to become the TILs that have been modified.”
Claim 15 recites the limitation "the mean diameter" in line 3. There is insufficient antecedent basis for this limitation in the claim.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 8 and 10-11 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 8, which depends from claim 7, recites the limitation “wherein the modifying further comprises contacting the TILs with the nucleic acid encoding the co-stimulatory molecule and/or the nucleic acid encoding the cytokine.” However, this limitation is already recited in lines 3-5 of claim 7.
Claim 10, which depends from claim 9, recites the limitation “further comprising contacting the cell suspension with the nucleic acid encoding the co-stimulatory molecule and/or the nucleic acid encoding the cytokine.” However, this limitation is already recited in lines 3-5 of claim 9.
Claim 11 depends from claim 10, and therefore inherits its deficiency.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102
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)(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.
Claim(s) 1, 3-11, and 14-23 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Vogt (US 2024/0307437 A1), as evidenced by Sharei (US 2014/0287509 A1) and Tekguc (PNAS, 2021, 118 (30): e2023739118).
Vogt teaches compositions and methods for the treatment of cancers using modified TILS, wherein the modified TILS include one or more immunomodulatory agents, including cytokines, associated with their cell surface, and wherein the immunomodulatory agents enhance TIL survival, proliferation, and/or anti-tumor activity in a patient recipient (Abstract).
Vogt teaches a method of introducing nucleic acids encoding membrane-anchored immunomodulatory fusion proteins into a population of TILs to produce transiently modified or genetically modified TILs that express the membrane anchored immunomodulatory fusion (para 221, 699). Vogt teaches that in some embodiments, nucleic acids encoding the membrane anchored immunomodulatory fusion proteins are introduced into a population of TILs using a microfluidic platform, including a SQZ vector-free microfluidic platform (para 699).
Specifically, Vogt teaches a method of producing modified TILs with membrane anchored IL-2 and IL-12 immunomodulatory fusion proteins (Example 13, para 3676-3679). Vogt teaches delivering mRNA encoding membrane anchored IL-2 and/or IL-12 (claims 6, 14) to subpopulations of the TILs using the SQZ method (also referred to therein as “Squeezing”) (para 3676) (step (a) of claim 1; claim 20). Vogt teaches that in the SQZ platform, the cell membranes of the cells for modification (e.g., TILs) are temporarily disrupted by microfluidic constriction (reads on passing a cell suspension comprising the TILs through a cell-deforming constriction of claims 7, 9, 21), thereby allowing the delivery of nucleic acids encoding the membrane anchored immunomodulatory fusion proteins into the cells (para 699) (claims 7-11, 14, 21-22). Following Squeezing, Vogt teaches resuspending and culturing the TILs for 4 days (claim 4) in CM2 media with or without 300 IU/mL of IL-2 (culturing without IL-2 reads on culturing the TILs in the absence of an exogenous cytokine of step (b) of claim 1 and of claim 20) (para 3676).
In Example 13, Vogt is silent regarding Granzyme B expression exhibited by the TILs after the modifying and culturing. However, because the method taught in Example 13 of Vogt reads on the method of instant claim 1, the method of Vogt would inherently result in TILs with increased Granzyme B expression upon activation (claim 1). Moreover, Vogt teaches that in some embodiments, Granzyme secretion of the expanded population of TILs is increased by at least one-fold to fifty-fold or more as compared to non-expanded population of TILs (para 2612) (claims 1, 3).
In Example 13, Vogt is silent regarding proliferation of the TILs after the modifying and culturing. However, because the method taught in Example 13 of Vogt reads on the method of instant claim 20, the method of Vogt would inherently result in TILs with increased proliferation upon activation (claim 20). Moreover, Vogt teaches that the method taught therein enhances proliferation in a patient recipient (e.g., Abstract; para 5, 67-68, 2509, 2532, 2290).
Vogt teaches that the SQZ vector-free microfluidic platform, as utilized in the disclosure therein, is described in publications, including U.S. Patent Application Publication No. US 2014/0287509A1 (herein after “Sharei”) (para 699). Sharei shows that the cell-deforming constriction comprises a width which is less than the diameter of the cell, such as a width which is 20-99% of the diameter of the cell (para 8; also see para 95, 112, 151) (claims 15, 16). Sharei further shows that preferably, the width of the constricted portion of the conduit is no less than 4 μm in diameter (para 8), including embodiments that have a width which range from 4-8 μm (para 187, 211, 234) (claims 17-19, 23).
Regarding claim 5: Vogt teaches modified TILs that further comprise a genetic modification that causes expression of one or more immune checkpoint genes, including CTLA-4, to be silenced or reduced in at least a portion of the therapeutic population of TILs (para 206, 728, 1277-1278, 1292-1293). Tekguc shows that CTLA-4 downregulates CD86 (e.g., Abstract, Discussion). Therefore, a cell which has been modified to have reduced expression of CTLA-4 would have increased expression of CD86.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Risa Takenaka whose telephone number is (571)272-0149. The examiner can normally be reached M-F, 12-7 EST.
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/RISA TAKENAKA/Examiner, Art Unit 1632
/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632
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