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
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 July 14, 2026 has been entered.
Claim Status
Claims 1-2, 6-8, 10, 12-14, 19-22, and 24-25 have been amended.
Claims 5 and 17-18 were previously canceled.
Claim 31 has been added.
Claims 1-4, 6-16, and 19-31 are pending and under consideration.
Priority - Updated
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. This application is a continuation of U.S. Application No. 18/674,562 filed 05/24/2024, which claims the benefit of U.S. Application No. 18/256,798 filed 06/09/2023 (Abandoned), which is a 371 of PCT/US21/63910 filed 12/16/2021, which claims the benefit of U.S. Provisional Application No. 63/277,371 filed 11/09/2021, which claims the benefit of U.S. Provisional Application No. 63/146,425 filed 02/05/2021, which claims the benefit of U.S. Provisional Application No. 63/127,060 filed 12/17/2020.
Support for the inventions encompassed by claims 1 and 7-13 can be found in the 63/127,060 provisional application filed 12/17/2020.
However, Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
Claims 2-3 and 19 are drawn to NSCLC patients with a predetermined absence of one or more driver mutations.
Claims 4 and 16 are drawn to NSCLC patients with a tumor proportion score (TPS) of <1%.
Claims 6 and 24 recite that a dose of pembrolizumab is administered after tumor resection and prior to TIL transfer. However, prior applications 63/127,060 and 63/146,425 only contemplate administering pembrolizumab before tumor resection.
Claims 14 and 20 recite the NSCLC is metastatic non-small cell lung cancer. None of the prior applications or current specification provide support for treatment of metastatic NSCLC (see new matter rejection below under 35 U.S.C. 112(a)).
Prior applications 63/127,060 and 63/146,425 do not disclose the subject matter of the presently claimed invention encompassed by claims 2-4, 6, 16, 19, and 24. Specifically, the prior applications do not contemplate the method to be used on NSCLC patients with the absence of at least one driver mutation or with a TPS of <1%, wherein pembrolizumab is administered after tumor resection and prior to TIL transfer. The first disclosure of the limitations as recited is in provisional application 63/277,371 filed 11/9/2021.
Should Applicant disagree with the examiner’s factual determination as to the disclosure of the various claim limitations, Applicant may point out the particular places within applications 63/127,060 and 63/146,425 which discloses the specific subject matter.
Accordingly, claims 1 and 7-13 have an earliest effective filing date of 12/17/2020, corresponding to provisional application 63/127,060; claims 2-4 and 6 have an earliest effective filing date of 11/9/2021, corresponding to provisional application 63/277,371; and claims 14-16 and 19-31 have an earliest effective filing date of 9/16/2024, corresponding to the filing date of the instant application.
Information Disclosure Statement
The information disclosure statement (IDS) submitted 8/7/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections - Withdrawn
In view of Applicant’s amendments, the previous objections to the claims for minor informalities have been withdrawn.
Claim Rejections - 35 USC § 112(b) - New
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.
Claims 1-4, 6-13, 19, and 24 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 1 (lines 8-9) recite “wherein a first amount of a non-myeloablative lymphodepletion regimen is administered to the patient or subject”. The recitation of the phrase “a first amount” suggests that more than one non-myeloablative lymphodepletion regimen is administered to the subject, however, there is no mention of administering a second amount, making the scope of the claims unclear. For the purposes of examination, the claims are interpreted as a single round of non-myeloablative lymphodepletion regimen is administered to the subject prior to TIL transfer.
Claims 2-4 and 6-13 are included in the rejection because they depend from or otherwise require all the limitations of the rejected claim but fail to clarify the issue.
Claim 1 (line 8) recites “administration of an amount of pembrolizumab”, which is ambiguous. The claim should be amended to recite “administration of a therapeutically effective amount of pembrolizumab”.
Claims 2-4, 6-7, and 9-13 are included in the rejection because they depend from or otherwise require all the limitations of the rejected claim but fail to clarify the issue.
Claims 2 and 19 recite the driver mutation, “a c-ROS mutation (ROS1 mutation)”. However, the parenthetical ROS1 mutation suggests a particular targeted mutation, not just a c-ROS mutation. The claims will be interpreted as a predetermined absence of a ROS1 driver mutation, and not c-ROS mutations broadly.
Claim 3 is included in the rejection because it depends from or otherwise requires all the limitations of the rejected claim but fails to clarify the issue.
Claims 6 and 24 recite “further comprising administering an additional dose of pembrolizumab to the patient or subject after resection of a tumor sample from the patient or subject for manufacture of the therapeutic population of TILs and before the patient or subject is treated with the non-myeloablative lymphodepletion regimen”. The term “additional” suggests a sequential order of administration, (i.e., after a first administration). However, the independent claim in which claims 6 and 24 depend from recite pembrolizumab is administered after TIL transfer. Thus, it is unclear how an additional dose can be administered prior to the first dose. It is suggested that the word “additional” be deleted so that the claims read “further comprising administering a dose of pembrolizumab…”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(d) - New
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.
Claims 15-16 and 20 are rejected under 35 U.S.C. 112(d) 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 15 recites the NSCLC is anti-PD-1/PD-L1 naïve, however, the claim depends from claim 14 which recites a method of treating metastatic non-small cell lung carcinoma (NSCLC) in a patient who has received no prior PD-1 therapy and no prior PD-L1 therapy. Accordingly, claim 15 fails to further limit claim 14.
Claim 16 is included in the rejection because it depends from or otherwise requires all the limitations of the rejected claim but fails to clarify the issue.
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 20 recites the NSCLC is metastatic NSCLC, however, the claim depends from claim 14 which recites a method of treating metastatic non-small cell lung carcinoma (NSCLC). Accordingly, claim 20 fails to further limit claim 14.
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 § 112(a) – Withdrawn
The previous rejection of claims 1-4, 6-16, and 19-30 under 35 U.S.C. 112(a) for claiming new matter has been withdrawn in view of Applicant’s deletion wherein patients are administered one or more PD-L1 inhibitors for the treatment of NSCLC.
Claim Rejections - 35 USC § 112(a) – Written Description – New
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.
Claims 14-16 and 19-31 are rejected under 35 U.S.C. 112(a), first paragraph, as failing to comply with the written description requirement. The claims contain 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 at the time the application was filed, had possession of the claimed invention.
Claim 14 is drawn to methods of treating metastatic non-small cell lung carcinoma (NSCLC) in a subject or patient who has received no prior PD-1 therapy and no prior PD-L1 therapy, the method comprising several steps, including administering a therapeutically effective amount of pembrolizumab every six weeks after TIL transfer.
Applicant has disclosed methods of treating NSCLC by administering TILs in combination with pembrolizumab. However, none of the prior applications or the instant specification disclose the subject matter of the presently claimed invention. Specifically, there is no mention or contemplation of a treatment for metastatic NSCLC comprising administering TILs in combination with pembrolizumab.
In fact, the previous and instant disclosures only recite methods of treating metastatic NSCLC comprising administering TILs in combination with nivolumab and ipilimumab [01257; 12/17/2020], [01282; 2/5/2021], [01650; 11/9/2021], [01652; 9/16/2024]. This is an important distinction because Applicant has disclosed a number of patentably distinct treatment methods for a variety of solid tumors. The specific immune checkpoint inhibitor(s) to be used to treat each tumor type are set forth in detailed methods disclosed within the 551 page specification. None of these methods include treatment of metastatic NSCLC with TIL therapy in combination with pembrolizumab administration.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with
reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession
of the invention. The invention is, for purposes of the 'written description’ inquiry, whatever is now
claimed." (See Vas-Cath, p. 1117). The specification does not "clearly allow persons of ordinary skill in
the art to recognize that [he or she] invented what is claimed." (See Vas-Cath, p. 1116). Meeting the written description threshold requires showing that the applicant was in “possession” of the claimed invention at the time of filing. Vas-Cath, 935 F.2d at 1563-1564. Support need not describe the claimed subject matter in exactly the same terms as used in the claims. Eiselstein v. Frank, 52 F.3d 1035, 1038 (Fed. Cir. 1995). This support cannot be based on obviousness reasoning — i.e., what the written description and knowledge in the art would lead one to speculate as to modifications the inventor might have envisioned, but failed to disclose. Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572 (Fed. Cir. 1997).
Claims 15-16 and 19-31 are included in the rejection because they depend from or otherwise require all the limitations of a rejected independent claim.
Claim Rejections - 35 USC § 102 – Withdrawn
In view of Applicant’s amendments to claim 1 perfecting the priority date, the previous rejection of claims 1, 4, 6, 8-10, and 12-13 under 35 U.S.C. 102(a)(1) as being anticipated by Schoenfeld has been withdrawn.
Claim Rejections - 35 USC § 103 - Updated
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.
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.
Claims 1, 6-10, and 12-13 are rejected under 35 U.S.C. 103 as being unpatentable over Chesney et al. (ASCO 2019, Poster No. 290a) (“Chesney”), in view of Federal Drug Administration Notice (“FDA approves new dosing regimen for pembrolizumab”; April 29, 2020) (“FDA”).
The instant claims are drawn to a method of treating non-small cell lung carcinoma (NSCLC) in a patient or subject who has received no prior PD-1 therapy and no prior PD-L1 therapy comprising administering to the patient or subject a therapeutically effective amount of a therapeutic population of tumor infiltrating lymphocytes (TILs) and a therapeutically effective amount of pembrolizumab, wherein a non-myeloablative lymphodepletion regimen is administered to the patient or subject in advance of the administration of the TILs, and administering pembrolizumab every six weeks after the administration of the TILs, wherein pembrolizumab is administered by intravenous infusion at a dosage of 400 mg every six weeks for up to 2 years, and wherein the non-myeloablative lymphodepletion regimen comprises cyclophosphamide at a dose of 60 mg/kg/day for two days followed by administration of fludarabine at a dose of 25 mg/m2/day for five days prior to TIL treatment, followed by an IL-2 regimen starting three to twenty-four hours after administration of a therapeutically effective amount of the population of TILs.
Chesney discloses administration of autologous tumor infiltrating lymphocytes (TIL) in combination with pembrolizumab for the treatment of non-small cell lung cancer (NSCLC) solid tumors (instant claim 1 partial). TIL transfer has demonstrated durable complete responses in immunogenic tumors with high mutational burden, and the presence of TIL in the tumor microenvironment (TME) is correlated with long term response and survival. Addition of pembrolizumab to TIL therapy further enhances treatment prior and post TIL infusion by assisting trafficking into the tumor and dampening TME suppressor mechanisms, respectively [Background].
Chesney discloses the treatment protocol for Cohort 3A comprising patients with NSCLC that are checkpoint inhibitor naïve [Study Design, Fig. 2; Inclusion Criteria] (instant claim 1 partial). Patients are treated with a nonmyeloablative lymphodepletion regimen one to seven days prior to TIL transfer comprising cyclophosphamide (60 mg/kg x 2 days) and fludarabine (25 mg/m2 x 5 days) (instant claim 13). Patients in Cohort 3A receive an initial dose of 200 mg IV pembrolizumab between tumor resection and initiation of the nonmyeloablative lymphodepletion (instant claims 6-7). Following TIL transfer, patients receive 6 doses of IL-2 (600,000 IU/kg) starting at Day 1 (instant claim 10). Patients continue to receive 200 mg IV pembrolizumab every three weeks (Q3W) for 24 months, or until disease progression or unacceptable toxicity, following IL-2 completion [Study Flowchart] (instant claim 12).
Chesney teaches administering pembrolizumab every three weeks, but does not teach administering pembrolizumab every six weeks.
The FDA teaches a new 400 mg Q6W dosing regimen for pembrolizumab was approved across all currently approved adult indications under accelerated approval based on pharmacokinetic data, the relationship of exposure to efficacy, and the relationship of exposure to safety (instant claim 1 partial, claims 9-10). The FDA teaches the 400 mg Q6W dosing regimen is as safe and effective as the previously approved 200 mg Q3W dosing regimen. The accelerated approval was driven by the COVID-19 pandemic, as this would significantly lessen the burden on the patient (i.e., number of injections, time for travel for treatment) and fewer number of treatments would lessen patients’ exposure and risk of contracting the virus.
As such, it would have been obvious to one of ordinary skill in the art that pembrolizumab can be administered every 6 weeks at a dose of 400 mg rather than 200 mg administered every three weeks as taught by Chesney based on the safety and efficacy data released by the FDA.
One would be motivated to do so at the time the invention was made due to the ongoing COVID-19 pandemic, by cutting the number of patient visits in half which would necessarily reduce the risk of contracting COVID-19. One of ordinary skill would have more than a reasonable expectation of success in following the Q6W treatment schedule based on the FDA report which approved the Q6W dosing regimen across all adult indications.
Section 2144.06 of the MPEP provides guidance as to obviousness of art recognized equivalents for the same purpose. The court has held that it is obvious to combine two elements each of which is taught by the prior art to be useful for the same purpose. No specific teaching or suggestion is needed for combination – the idea of combining them flows logically from their having been individually taught in the prior art as useful for the same purpose. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that if a technique has been used to improve one method, and a person of ordinary skill would recognize that it would be used in similar methods in the same way, using the technique is obvious unless its application is beyond that person’s skill. It would be obvious to apply a known technique to a known product to be used in a known method that is ready for improvement to yield predictable results. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.
Therefore, the instant invention was prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention in view of the combined references.
Claims 2-4 are rejected under 35 U.S.C. 103 as being unpatentable over Chesney et al. (ASCO 2019, Poster No. 290a) (“Chesney”), in view of Federal Drug Administration Notice (“FDA approves new dosing regimen for pembrolizumab”; April 29, 2020) (“FDA”) as applied to claims 1, 6-10, and 12-13 above, and in further view of Slater (CancerNetwork, Oct. 4, 2020; www.cancernetwork.com/ view/study-supports-pembrolizumab-plus-chemo-as-standard-of-care-for-pd-l1-negative-advanced-nsclc) (“Slater”), Clinical Trial NCT02578680 (v.46; 2018-10-29), and Clinical Trial NCT02775435 (v.45; 2019-03-18).
The instant claims are drawn to a method of treating non-small cell lung carcinoma (NSCLC) in a patient or subject who has received no prior PD-1 therapy and no prior PD-L1 therapy comprising administering to the patient or subject a therapeutically effective amount of a therapeutic population of tumor infiltrating lymphocytes (TILs) and a therapeutically effective amount of pembrolizumab, wherein a non-myeloablative lymphodepletion regimen is administered to the patient or subject in advance of the administration of the TILs, and administering pembrolizumab every six weeks after the administration of the TILs, wherein the subject or patient has a predetermined absence of one or more driver mutations, wherein the driver mutation is selected from the group recited in claim 2, specifically, wherein the driver mutation is an EGFR mutation, and the NSCLC is PD-L1 negative as determined by a tumor proportion score (TPS) of < 1%.
The teachings of Chesney are set forth above.
Chesney does not explicitly teach the subject or patient has a predetermined absence of one or more driver mutations or is PD-L1 negative as determined by a tumor proportion score (TPS) of < 1%.
Slater teaches pembrolizumab plus chemotherapy as a treatment for patients with PD-L1-negative advanced non-small cell lung cancer (NSCLC) without EGFR/ALK alterations [par. 1] (instant claims 2-3, 4 partial). Slater pooled data from three separate clinical trials comprising patients with squamous and nonsquamous NSCLC (NCT02039674, NCT02578680, NCT02775435) [par. 4]. In total, 444 of 1328 patients (33.4%) who were enrolled across the 3 trials were found to have PD-L1‒negative tumors [par. 5]. Of those with PD-L1-negative tumors, the ORR was higher with pembrolizumab plus chemotherapy (50.0%; 95% CI,43.7%-56.3%) compared with chemotherapy alone (29.8%; 95%CI, 23.4%-36.9%) [par. 8]. Moreover, 16 patients in the pembrolizumab plus chemotherapy arm completed 2 years of treatment; the ORR was 87.5% (95% CI, 61.7%-98.4%), and the 3-year OS rate was 100% [par. 9].
Treatment with pembrolizumab plus chemotherapy significantly reduced the risk of death and improved the median OS by approximately 8 months (19.0 vs 11.4 months). Patients who completed 2 years of treatment were among those who acquired a long-term benefit from pembrolizumab plus chemotherapy; ORR was high among those in this group, and all patients remained alive at the time of the individualized data cutoffs [par. 2].
Slater teaches that there are few treatment options for patients with PD-L1 negative NSCLC, however pembrolizumab plus chemotherapy provides a clinically meaningful OS benefit in this population, supporting pembrolizumab plus chemotherapy as a standard of care first-line treatment for patients with PD-L1 negative advanced NSCLC without EGFR/ALK alterations [par. 3].
Slater teaches PD-L2 negative advanced NSCLC, but is silent in how the negative status was determined for the three clinical trials (NCT02039674, NCT02578680, NCT02775435) in which the teachings rely.
Clinical Trials NCT02578680 and NCT02775435 teach participants were assessed for their PD-L1 tumor expression level by immunohistochemistry assay using tumor tissue from a newly obtained biopsy. Participants with a TPS ≥1% were classified as PD-L1 positive and participants with a TPS <1% were classified as PD-L1 negative [Baseline Characteristics] (instant claim 4).
The teachings of Chesney differ from the present invention in that although administration of TIL + pembrolizumab in combination with nonmyeloablative lymphodepletion and IL-2 regimens for the PD-1/PD-L1 treatment naïve NSCLC is taught, the patients are not explicitly taught as having PD-L1 negative tumors lacking EGFR or ALK alterations. Given that Chesney teaches pembrolizumab + TIL therapy can be used to treat patients with advanced NSCLC, a skilled artisan would have a reasonable expectation of success that the combination treatment would also be effective in NSCLC patients with negative PD-L1 expression, as this population makes up a majority of NSCLC cases (> 33% of all patients) because there is no teaching away or discouragement that the methods of Chesney would not be applicable to patients with PD-L1 negative expression (i.e., exclusion criteria). MPEP § 2145(X)(D) states, "a reference does not teach away if it merely expresses a general preference for an alternative invention but does not criticize, discredit or otherwise discourage investigation into the invention claimed.", DePuy Spine, Inc. v. Medtronic Sofamor Danek, Inc., 567 F.3d 1314, 1327 (Fed. Cir. 2009); and Schwendimann v. Neenah, Inc., 82 F.4th 1371, 1381, 2023 USPQ2d 1173 (Fed. Cir. 2023).
Additionally, Slater teaches that a majority of patients over three clinical trials were PD-L1 negative lacking EGFR driver mutations. The patients who received pembrolizumab in addition to chemotherapy saw an astounding increase in overall survival compared to the chemotherapy alone. Two of the three clinical trials taught by Slater specify methods of determining PD-L1 negative expression by measuring the tumor progression score (TPS) via IHC, wherein a TPS <1% indicates negative PD-L1 expression. As such, determining PD-L1 expression via IHC analysis and quantification of a TPS score was routine in the before the effective filing date of the claimed invention as evidenced by Clinical Trials NCT02578680 and NCT02775435 that quantified TPS scores from IHC of tumor tissue obtained from patients with NSCLC.
Section 2144.06 of the MPEP provides guidance as to obviousness of art recognized equivalents for the same purpose. The court has held that it is obvious to combine two elements each of which is taught by the prior art to be useful for the same purpose. No specific teaching or suggestion is needed for combination – the idea of combining them flows logically from their having been individually taught in the prior art as useful for the same purpose. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
Moreover, Slater teaches PD-L1 negative advanced NSCLC patients without EGFR/ALK alterations saw significantly higher clinical benefit and survival rates when pembrolizumab was added in combination with chemotherapy, providing motivation to treat these patients with the protocols of Chesney because advanced NSCLC patient have few treatment options and poor overall survival (See MPEP § 2143(E)). The encouraging 2+ year survival rate in this population would provide further motivation to add pembrolizumab to a therapy comprising TIL transfer. Therefore, the instant invention was prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention in view of the combined references.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Chesney et al. (ASCO 2019, Poster No. 290a) (“Chesney”), in view of Federal Drug Administration Notice (“FDA approves new dosing regimen for pembrolizumab”; April 29, 2020) (“FDA”) as applied to claims 1, 6-10, and 12-13 above, and in further view of Fardis et al. (WO 2020/096989 A1; cited IDS 9/16/2024) (“Fardis”).
The instant claims are drawn to a method of treating non-small cell lung carcinoma (NSCLC) in a patient or subject who has received no prior PD-1 therapy and no prior PD-L1 therapy comprising administering to the patient or subject a therapeutically effective amount of a therapeutic population of tumor infiltrating lymphocytes (TILs) and a therapeutically effective amount of pembrolizumab, wherein a non-myeloablative lymphodepletion regimen is administered to the patient or subject in advance of the administration of the TILs, and administering pembrolizumab every six weeks after the administration of the TILs, comprising further administration of an IL-2 regimen starting three to twenty-four hours after administration of the TILs, wherein the IL-2 regimen is a high-dose IL- 2 regimen comprising up to six doses of 600,000 IU/kg of aldesleukin administered as a 15- minute bolus intravenous infusion every eight to twelve hours.
The teachings of Chesney are set forth above, including, following TIL transfer, patients receive 6 doses of IL-2 (600,000 IU/kg) starting at Day 1 [Study Flow Chart].
Chesney does not teach the IL-2 is administered as a 15- minute bolus intravenous infusion every eight to twelve hours.
Fardis teaches detailed methods for transfer of autologous tumor infiltrating lymphocytes (TILs) comprising a high-dose IL-2 regimen comprising 600,000 IU/kg of aldesleukin administered as a I5-minute bolus intravenous infusion every eight hours until tolerance (claim 40).
It would have been obvious at the time of filing the instant invention to combine the protocols of Chesney with those of Fardis. Chesney teaches administering TIL in combination with pembrolizumab for treating NSCLC in PD-1/PD-L1 treatment naïve patients, however, does not provide timing or duration of IL-2 administration. Methods for treatment with autologous TIL that include IL-2 administration post transfer were known in the art at the time of filing, and a skilled artisan would easily be able to obtain detailed protocols for TIL production and transfer as evidenced by Fardis. 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.
Claims 14-16 and 19-31 are rejected under 35 U.S.C. 103 as being unpatentable over Schoenfeld et al. (IASLC 2023, Conference Presentation) (“Schoenfeld”), in view of Fardis et al. (WO 2020/096989 A1; cited IDS 9/16/2024) (“Fardis”).
The instant claims are drawn to a method of treating metastatic non-small cell lung carcinoma (NSCLC) in a patient or subject who has received no prior PD-1 therapy and no prior PD-L1 therapy comprising administering to the patient or subject a therapeutically effective amount of a therapeutic population of tumor infiltrating lymphocytes (TILs) and a therapeutically effective amount of pembrolizumab, wherein a non-myeloablative lymphodepletion regimen is administered to the patient or subject in advance of the administration of the TILs, and administering pembrolizumab every six weeks after the administration of the TILs, wherein the NSCLC is PD-L1 negative with a tumor progression score (TPS) <1% and has a predetermined absence of an EGFR mutation or insertion. Further comprising treating the patient with a non-myeloablative lymphodepletion regimen comprising cyclophosphamide at a dose of 60 mg/kg/day for two days followed by administration of fludarabine at a dose of 25 mg/m2/day for five days prior to TIL treatment, treating the patient with an IL-2 regimen starting three to twenty-four hours after administration of the TILs, wherein the IL-2 regimen is a high-dose IL-2 regimen comprising up to six doses of 600,000 IU/kg of aldesleukin administered as a 15-minute bolus intravenous infusion every eight to twelve hours until tolerance. The method comprising obtaining a first population of TILs from a tumor resected from a patient, performing a first expansion by culturing the first population of TILs in a cell culture medium comprising IL-2 to produce a second population of TILs, wherein the first expansion is performed for about 3-14 days to obtain the second population of TILs; performing a second expansion by supplementing the cell culture medium of the second population of TILs with additional IL-2, OKT-3, and antigen presenting cells (APCs), to produce a third population of TILs, wherein the second expansion is performed for about 7-14 days to obtain the third therapeutic population of TILs, harvesting the therapeutic population of TILs, and administering a therapeutically effective amount of pembrolizumab every six weeks after TIL transfer; wherein the first expansion is performed over a period of about 11 days and the second expansion is performed over a period of about 11 days.
Schoenfeld teaches IOV-COM-202 (NCT03645928), a global phase 2, multicenter, multicohort open-label study of autologous TIL cell therapy in patients with solid tumors. Cohort 3A includes patients with anti–PD-1/PD-L1 naïve locally advanced or metastatic NSCLC with disease progression treated with TIL (LN-145) plus pembrolizumab [Methods and Objective] (instant claim 14 partial, claims 15, 20).
[Fig. 1] – Schoenfeld teaches the treatment schema for the study, comprising tumor tissue procurement, followed by a single dose of pembrolizumab (200 mg or 400 mg) (instant claim 14 partial, claim 24). Patients undergo non-myeloablative lymphodepletion starting 7 days prior to TIL transfer, comprising cyclophosphamide 60 mg/kg/day for two days followed by administration of fludarabine at a dose of 25 mg/m2/day for five days (instant claim 14 partial, claim 25). Schoenfeld further teaches on Day 0 or 1 (i.e., within 24 hours) following TIL transfer an IL-2 regimen comprising up to six doses of 600,000 IU/kg of IL-2 (instant claim 26, claim 27 partial). Pembrolizumab is administered Q3W (200 mg) or Q6W (400 mg) for ≤24 months following the IL-2 regimen (instant claim 14 partial, claims 21-23, 31).
Schoenfeld teaches baseline patient and disease characteristics for Cohort 3A (n=19). Patients were largely PD-L1 negative, with high burden of disease [pg. 2, last col.]. Over 68% of the patients (n=13) were PD-L1 negative with a tumor proportion score <1% (instant claim 16). Patients were also screened for driver mutations in BRAF, EGFR, ALK, ROS1, KRAS, and NTRK. Eight of the patients with PD-L1-negative disease were EGFR wild-type (instant claim 19).
Schoenfeld teaches that in patients with ICI-naïve metastatic NSCLC, activity of TILs plus pembrolizumab was greater than what has previously been reported for TIL LN‐145 monotherapy or pembrolizumab alone and was not limited by PD-L1 TPS. Patients saw durable and deepening responses (up to 15.4 months and ongoing) and TIL clones persisted after infusion [Trial Conclusions].
Schoenfeld differs from the present invention in that although TIL therapy in combination with pembrolizumab for the treatment of metastatic NSCLC is taught, the specific methods for TIL manufacturing are not.
Methods for TIL procurement and manufacturing were routine for one of skill in the art at time of the effective filing date of the instant invention and would have been obvious to one of ordinary skill in the art as expanding TILs via multiple cycles would lead to a higher number of TILs capable of infiltrating the tumor cells.
For example, Fardis teaches methods of treating non-small cell lung carcinoma (NSCLC) with a population of tumor infiltrating lymphocytes (TILs) wherein the patient has not been previously treated with an anti-PD-1 and/or anti-PD-L1 antibody and has low expression of PD-L1 (claim 11).
Specifically, Fardis teaches in Figure 8A, the 22-day process beginning with obtaining the patient tumor sample; cutting the tumor into fragments and a first expansion of 3-14 days in IL-2 rich media; a second expansion in media supplemented with IL-2, OKT-3, and APCs; and harvesting the TILs (instant claim 14 partial). The second expansion can proceed for 7-14 days [00538]. The first expansion can be shortened to 11 days, such as the combination of the first and second expansion totals 22 days [00492] (instant claims 28-30). In addition, Fardis teaches the high-dose IL-2 regimen comprising 600,000 IU/kg of aldesleukin administered as a 15-minute bolus intravenous infusion every eight hours until tolerance (claim 40) (instant claim 27).
It would have been obvious at the time of filing the instant invention to combine the protocols of Chesney with those of Fardis. Chesney teaches administering TIL in combination with pembrolizumab for treating NSCLC in PD-1/PD-L1 treatment naïve patients, however, does not provide timing or duration of IL-2 administration or a detailed protocol for TIL production. Methods for treatment with autologous TIL that include IL-2 administration post transfer were known in the art at the time of filing, and a skilled artisan would easily be able to obtain detailed protocols for TIL production and transfer as evidenced by Fardis. Therefore, the instant invention was prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention in view of the combined references.
Applicant’s Arguments
Applicant has argued on page 9-10 of the reply received July 14, 2026 that the previous rejections of claims 1-16 and 19-30 under 35 U.S.C. 103 should be withdrawn because the claims have been amended as such that the obviousness rejections no longer apply.
Response to Arguments
Applicant’s arguments with respect to claims 1-16 and 19-30 have been considered but are not persuasive because the claims have been amended as such that the new grounds of rejection rely on the previous references applied in the prior rejections, but presented in a different order.
Double Patenting – Maintained/Updated
Pursuant to 37 CFR 1.78(f), when two or more applications filed by the same applicant or assignee contain patentably indistinct claims, elimination of such claims from all but one application may be required in the absence of good and sufficient reason for their retention during pendency in more than one application. Applicant is required to either cancel the patentably indistinct claims from all but one application or maintain a clear line of demarcation between the applications. See MPEP § 822.
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.
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Claims 1-4 and 6-13 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4, 15-16, 18, 40, and 91 of copending Application No. 18/247,877, in view of Chesney et al. (ASCO 2019, Poster No. 290a) (“Chesney”), in view of FDA Notice (“FDA approves new dosing regimen for pembrolizumab”; April 29, 2020) (“FDA”).
Copending claim 1 recites a method of treating non-small cell lung carcinoma (NSCLC) by administering a population of tumor infiltrating lymphocytes (TILs) to a subject in need thereof, wherein the subject has a predetermined absence of one or more driver mutations and a predetermined tumor proportion score (TPS) of PD-L1 of< 1% , wherein the one or more driver mutations comprise one or more of an epidermal growth factor receptor (EGFR) mutation, an anaplastic lymphoma kinase (ALK) mutation, or a ROS 1 mutation. Copending claim 90 recites wherein the one or more driver mutations comprise an EGFR mutation. Copending claims 2 and 4 recite methods for TIL manufacturing that are identical to those recited in the instant claims. Copending claim 15 recites the subject has a TPS of PD-L1 of< 1% and has a predetermined absence of one or more driver mutations. Copending claim 16 recites types of driver mutations. Copending claim 18 recites the NSCLC has low or no expression of PD-L1. Copending claim 40 recites the NSCLC has not been previously treated with an anti- PD-1 and/or anti-PD-L1 antibody.
The instant claims differ from the copending claims in that they do not disclose methods comprising non-myeloablative lymphodepletion, IL-2 regimen, or dosing for pembrolizumab.
The teachings of Chesney and the FDA presented above remedy these deficiencies.
Chesney teaches detailed protocols for the administration of TIL + pembrolizumab in combination with nonmyeloablative lymphodepletion and IL-2 regimens for the treatment of anti-PD-1/PD-L1 naïve NSCLC patients while the FDA provides evidence as to why pembrolizumab would be administered at Q6W (400 mg) versus Q3W (200 mg). As such, it would have been obvious to one of ordinary skill in the art that pembrolizumab can be administered every 6 weeks at a dose of 400 mg rather than 200 mg administered every three weeks as taught by Chesney based on the safety and efficacy data released by the FDA. One would be motivated to do so at the time the invention was made due to the ongoing COVID-19 pandemic, by cutting the number of patient visits in half which would necessarily reduce the risk of contracting COVID-19. One of ordinary skill would have more than a reasonable expectation of success in following the Q6W treatment schedule based on the FDA report which approved the Q6W dosing regimen across all adult indications. Thus, the instant claims are rendered obvious by the copending claims in view of Chesney and the FDA.
This is a provisional statutory double patenting rejection.
Claims 14-16 and 19-31 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4, 15-16, 18, 40, and 91 of copending Application No. 18/247,877, in view of Schoenfeld et al. (IASLC 2023, Conference Presentation) (“Schoenfeld”).
Copending claim 1 recites a method of treating non-small cell lung carcinoma (NSCLC) by administering a population of tumor infiltrating lymphocytes (TILs) to a subject in need thereof, wherein the subject has a predetermined absence of one or more driver mutations and a predetermined tumor proportion score (TPS) of PD-L1 of < 1% , wherein the one or more driver mutations comprise one or more of an epidermal growth factor receptor (EGFR) mutation, an anaplastic lymphoma kinase (ALK) mutation, or a ROS 1 mutation. Copending claim 90 recites wherein the one or more driver mutations comprise an EGFR mutation. Copending claims 2 and 4 recite methods for TIL manufacturing that are identical to those recited in the instant claims. Copending claim 15 recites the subject has a TPS of PD-L1 of< 1% and has a predetermined absence of one or more driver mutations. Copending claim 16 recites types of driver mutations. Copending claim 18 recites the NSCLC has low or no expression of PD-L1. Copending claim 40 recites the NSCLC has not been previously treated with an anti- PD-1 and/or anti-PD-L1 antibody.
The instant claims differ from the copending claims in that they do not disclose methods comprising non-myeloablative lymphodepletion, IL-2 regimen, or dosing for pembrolizumab, or that the method is for the treatment of metastatic NSCLC.
The teachings of Schoenfeld presented above remedy these deficiencies.
Schoenfeld teaches the treatment schema for the treatment of metastatic NSCLC, comprising tumor tissue procurement, followed by a single dose of pembrolizumab (200 mg or 400 mg). Patients undergo non-myeloablative lymphodepletion starting 7 days prior to TIL transfer, comprising cyclophosphamide 60 mg/kg/day for two days followed by administration of fludarabine at a dose of 25 mg/m2/day for five days. Schoenfeld further teaches on Day 0 or 1 (i.e., within 24 hours) following TIL transfer an IL-2 regimen comprising up to six doses of 600,000 IU/kg of IL-2. Pembrolizumab is administered Q3W (200 mg) or Q6W (400 mg) for ≤24 months following the IL-2 regimen. Thus, the instant claims are rendered obvious by the copending claims in view of Schoenfeld.
This is a provisional statutory double patenting rejection.
Claims 1-4, 6-15, and 19-31 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8, 17-18, 21, 29, 40, 85, and 316 of copending Application No. 18/849,440, in view of Chesney et al. (ASCO 2019, Poster No. 290a) (“Chesney”), in view of Federal Drug Administration Notice (“FDA approves new dosing regimen for pembrolizumab”; April 29, 2020) (“FDA”) and Fardis et al. (WO 2020/096989 A1; cited IDS 9/16/2024) (“Fardis”).
Copending claim 1 recites methods of manufacturing TILs from a subject with non-small cell lung cancer (NSCLC), wherein the patient is naïve to a cancer treatment, the method comprising:(a) prior to the subject receiving a cancer treatment, obtaining and/or receiving a first population of TILs from a tumor resected from the subject, processing a tumor sample obtained from the subject into multiple tumor fragments, wherein the first population of TILs is further expanded into a therapeutic population of TILs wherein the patient subject subsequently receives an ICI treatment and/or a standard of care treatment. Copending claim 8 recites the subject is naive to any ICI treatment. Copending claim 17 recites the subject is diagnosed with metastatic stage IV NSCLC. Copending claim 18 recite the subject has a predetermined tumor proportion score (TPS) of PD-L1 of < 1% and/or a predetermined absence of one or more driver mutations. Copending claim 21 recites multiple driver mutations, including EGFR mutations. Copending claim 29 recites the subject has not been previously treated with an anti-PD-1 and/or anti-PD-Li antibody. Copending claim 40 recites the NSCLC has not been previously treated with an anti-PD-1 and/or anti-PD-L1 antibody and has low or no expression of PD-L1. Copending claim 85 recites the subject subsequently receives first-line ICI treatment. Copending claim 316 recites the subject is treated with a non-myeloablative lymphodepletion regimen prior to administering the population of TILs to the subject, and/or treating the subject with an IL-2 regimen starting on the day after administration of the population of TILs to the subject or on the same day as administration of the population of TILs to the subject.
The claims of the copending application differ from the instant invention in that they do not recite the ICI is pembrolizumab, and no dosing is provided for the ICI, IL-2 regimen, or non-myeloablative lymphodepletion regimen. Additionally, the copending claims do not recite detailed methods for TIL manufacturing as recited in the instant claims.
The teachings of Chesney, the FDA, and Fardis remedy these deficiencies.
Chesney teaches detailed methods for the treatment of PD-1/PD-L1 treatment naïve NSCLC comprising administering TIL therapy in combination with pembrolizumab. Patients are treated with a nonmyeloablative lymphodepletion regimen one to seven days prior to TIL transfer comprising cyclophosphamide (60 mg/kg x 2 days) and fludarabine (25 mg/m2 x 5 days). Patients in Cohort 3A receive an initial dose of 200 mg IV pembrolizumab between tumor resection and initiation of the nonmyeloablative lymphodepletion. Following TIL transfer, patients receive 6 doses of IL-2 (600,000 IU/kg) starting at Day 1. Patients continue to receive 200 mg IV pembrolizumab every three weeks (Q3W) for 24 months, or until disease progression or unacceptable toxicity, following IL-2 completion [Study Flowchart].
Chesney teaches administering pembrolizumab every three weeks, but does not teach administering pembrolizumab every six weeks.
The FDA teaches a 400 mg Q6W dosing regimen for pembrolizumab was approved across all approved adult indications under accelerated approval based on pharmacokinetic data, the relationship of exposure to efficacy, and the relationship of exposure to safety. The FDA teaches the 400 mg Q6W dosing regimen is as safe and as effective as the previously approved 200 mg Q3W dosing regimen.
Fardis teaches a 22-day TIL manufacturing process beginning with obtaining the patient tumor sample; cutting the tumor into fragments and a first expansion of 3-14 days in IL-2 rich media; a second expansion in media supplemented with IL-2, OKT-3, and APCs; and harvesting the TILs. The second expansion can proceed for 7-14 days [00538]. The first expansion can be shortened to 11 days, such as the combination of the first and second expansion totals 22 days [00492]. In addition, Fardis teaches the high-dose IL-2 regimen comprising 600,000 IU/kg of aldesleukin administered as a 15-minute bolus intravenous infusion every eight hours until tolerance (claim 40)
As such, it would have been obvious to one of ordinary skill in the art that pembrolizumab would be the first line ICI therapy for the treatment of NSCLC. One of ordinary skill in the art would have a reasonable expectation of success in modifying the copending claims with the detailed protocols for TIL + pembrolizumab as taught by Chesney, and the detailed protocols for TIL manufacture taught by Fardis. One would be motivated to alter the dosing schedule of pembrolizumab, wherein it is administered every 6 weeks at a dose of 400 mg rather than 200 mg administered every three weeks based on the safety and efficacy data released by the FDA which approved the Q6W dosing regimen across all adult indications. Thus, the instant claims are rendered obvious by the copending claims in view of Chesney, the FDA, and Fardis
This is a provisional statutory double patenting rejection.
Conclusion
No claim is allowed.
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/MAUREEN VARINA DRISCOLL/ Examiner, Art Unit 1644
/SAMIRA J JEAN-LOUIS/ Supervisory Patent Examiner, Art Unit 1642
