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
Status of claims
The amendment filed on March 3, 2026 is acknowledged. Claims 2-9 and 15-22 have been withdrawn. Claims 1, 10-14, and 23-29 are under examination in the instant office action.
Applicants' arguments, filed on March 3, 2026, have been fully considered but they are not deemed to be persuasive. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied in view of amendments. They constitute the complete set presently being applied to the instant application.
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.
Claim 1, 10-14, and 23-29 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 pre-AIA the applicant regards as the invention. All the dependent claims are included.
The phrase, “favorable to immune modulation” in claim 1 can be relative based on which standard or factor is used. It is unclear which surrounding microenvironment is favorable to immune modulation because the claims do not provide a basis or standard for such determination. For example, if it is determined based on the Galon immunoscore system disclosed in the specification, what score range will be considered to be “favorable to immune modulation” as claimed. Also, if it is determined based on Fig. 6, the Fig. 6 is too complex and vague to clearly determine which surrounding microenvironment is favorable to immune modulation. The specification only provides a copy of the same figure from the Galon reference (Nature Reviews Drug Discovery volume 18, pages197–218, 2019; cited in the IDS) and does not provide any guidance how it is used to determine whether surrounding microenvironment is favorable to immune modulation based on those. There is no standard that is recognized in the art for measuring the meaning of the claimed term of degree.
In addition, it is not clear how to determine whether the cancer is immunogenic cancer and how to determine the chemotherapy regimen induces an immune-mediated response within the microenvironment. Further, the scope of immunogenic cancer and immunogenic cell death (ICD)-inducing chemotherapy is not clear. There is no well- established guidance to ascertain if a particular chemotherapeutic agent will be able to exert desired ICD-response and if a particular cancer is considered to be immunogenic cancer.
Also, the phrases, “high IFN-γ Signature” and “high Expanded Immune Signature” in claims 10 and 23 utilize a term of degree (“high”) and can be relative based on which standard or factor is used. The specification does not provide some standard for measuring the degrees intended. While “high” may be one higher than a baseline, the baseline is a subjective value. There is no standard that is recognized in the art for measuring the meaning of the claimed term of degree. As there are no objective boundaries for a “high IFN-γ Signature” and “high Expanded Immune Signature”, the metes and bounds are unclear. See MPEP 2173.05(b) I.
Response to Applicant’s arguments
Applicant argued that the phrase "favorable to immune modulation" would be readily understood by the skilled person working in the field of cancer and the specification provides multiple examples of how to determine this; for example, based on the Galon immunoscore system as set out in the application. Also, Applicants argued that the phrases "high IFN-γ signature" and "high expanded immune signature" would be readily understood by the skilled person working in the field of cancer. Applicants further stated that methods of determining whether a cancer patient meets these criteria would be immediately apparent to the skilled person and for example, the application teaches that a patient may be determined to have a high IFN-γ signature or expanded immune signature according to Ayer's IFN-γ Signature Score or Expanded Immune Signature Score.
In response, while Galon immunoscore system is one way of determining whether cancer has a surrounding microenvironment that is favorable to immune modulation, the claims are not limited to using such system. Also, even if it is determined based on the Galon immunoscore system disclosed in the specification, what score range will be considered to be “favorable to immune modulation” as claimed. If it is determined based on Fig. 6, the Fig. 6 is too complex and vague to clearly determine which surrounding microenvironment is favorable to immune modulation and does not provide any guidance how it is used to determine whether surrounding microenvironment is favorable to immune modulation based on those. The skilled artisan would not ascertain which cancer is embraced by the claimed phrase, thus the metes and bounds of the claimed cancer is unclear. There is no standard that is recognized in the art for measuring the meaning of the claimed term of degree. In addition, while Ayer's IFN-γ Signature Score can be used as Applicant asserted, the claims are not limited to using such score system only. Since there are no objective boundaries for a “high IFN-γ Signature” and “high Expanded Immune Signature”, the metes and bounds are unclear. See MPEP 2173.05(b) I.
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 of this title, 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.
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.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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, 10-14, and 23-29 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/106729 (hereafter, Sorrentino; cited in the IDS filed on 8/22/2022) and NCT02978716 clinical trial record history (5/23/2018) in view of Yeong et al. (Journal for Immunotherapy of Cancer, 7:34, Fe. 6, 2019).
Sorrentino teaches methods for treating a cancer or tumor in a subject by enhancing the pro-inflammatory microenvironment through the use of a regimented treatment protocol comprising the specifically-timed administration of a selective, fast-acting, short half-life CDK4/6 inhibitor in combination with a chemotherapeutic agent that is cytotoxic to immune effector cells, and an immune checkpoint inhibitor such as PD-1 inhibitor and PD-Ll inhibitor wherein the cyclin dependent kinase 4/6 (CDK4/6) inhibitor is
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(trilaciclib) and the chemotherapy is selected from carboplatin, cisplatin, oxaliplatin, 5-fluorouracil, floxuridine, capecitabine, gemcitabine, mytomycin, cyclophosphamide, decarbazine, abraxane, ifosfamide, topotecan, irinotecan, docetaxel, temozolomide, paclitaxel, and etoposide, pemetrexed or a combination thereof (abstract, p5, lines1-6, p10 lines 19-26, p16, lines 1-6, and claim 75-76). Carboplatin and gemcitabine are chemotherapies capable of inducing an immune-mediated responses and ICD-inducing chemotherapy as evidenced by the instant specification ([0056]).
Sorrentino further teaches that by using a CDK4/6 inhibitor during a chemotherapeutic agent/immune checkpoint inhibitor combination therapy regimen, immune effector cells such as T lymphocytes are protected from chemotherapeutic agent toxicity and released from a transient cell-cycle arrest in the presence of chemotherapy-induced immunogenic cell death, in a manner that provides for significantly improved priming and activation of an anti-cancer immune response and anti-cancer effect than without the use of a CDK4/6 inhibitor and anti-tumor activity is enhanced by cell cycle independent and dependent mechanisms, including the selective reduction of intra-tumoral Treg populations, preservation of pro-inflammatory immune effector cells such as tumor infiltrating lymphocytes, and an increased durability in treatment response (p5, lines 6-22).
Sorrentino discloses that in one embodiment, the CDK4/6 inhibitor is administered to the subject less than about 24 hours, 20 hours, 16 hours, 12 hours, 8 hours, or 4 hours, 2.5 hours, 2 hours, 1 hour, ½ hour or less prior to treatment with the chemotherapeutic agent (p11, line 15-p12, line 2).
Sorrentino further teaches that Compound I can result in gene expression changes that promote a pro-inflammatory tumor microenvironment favorable of response to immune checkpoint blockade (example 13) and leads to upregulation of interferon-gamma gene expression in tumor when added to oxaliplatin or oxaliplatin/anti-PD-Ll combinations (Example 14).
In addition, Sorrentino teaches that the cancer is selected from a small cell lung cancer, retinoblastoma, and triple negative (ER/PR/Her2 negative) or "basal-like" breast cancer (p66, lines 23-27).
Further, Sorrentino discloses that the combination of the Compound I with other chemotherapeutic agents resulted in improved overall survival compared to the chemotherapeutic agents alone (Examples 1-4 and Tables 1-3).
NCT02978716 discloses the clinical study of trilaciclib (T), a CDK4/6 inhibitor, in combination with gemcitabine (G), carboplatin (C) in metastatic triple negative breast cancer (mTNBC) (title). The study is to investigate the potential clinical benefit of trilaciclib in preserving the bone marrow and the immune system and enhancing chemotherapy antitumor efficacy when administered prior to gemcitabine and carboplatin (GC therapy) for patients with mTNBC (p3, brief summary). T was administered iv prior to GC infusion (p5, arm and intervention).
Sorrentino or NCT02978716 does not specifically teach that the cancer has a surrounding microenvironment favorable to immune modulation or TNBC being immunogenic or having a high IFN-γ signature.
It was known in the art that PD-1+ immune infiltrates, PD-L1 tumor cell expression and the expression of relevant genes including interferon gamma (IFNG) are positively associated with an improved clinical outcome of immunotherapy in TNBC as evidenced by Yeong et al. (abstract and conclusion). Yeong et al. teach that TNBC harbors relatively high numbers of tumor-infiltrating lymphocyte and expresses higher levels of PD-L1 compared to other breast cancer subtypes (p1, col2, last para-p2, col 1, para 1). Yeong et al. further teach that high expression of IFNG and IFN signaling genes was also associated with favorable disease-free survival (DFS) (abstract and Fig. 3h-i). TNBC having PD-1+ immune infiltrates and high expression of IFNG is a cancer having a surrounding microenvironment favorable to immune modulation or immunogenic cancer as claimed.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to select patients who are more likely to respond to the combination disclosed in Sorrentino or NCT02978716 for cancer immunotherapy by assessing known prognostic markers such as PD-1 and IFNG in the treatment of cancer such as TNBC because of the following reasons. It was already taught that CDK4/6 inhibitor in combination with a chemotherapeutic agent such as carboplatin and gemcitabine and an immune checkpoint inhibitor such as PD-Ll inhibitor significantly improved priming and activation of an anti-cancer immune response and anti-cancer effect in the treatment of cancers including TNBC. Sorrentino also teaches that Compound I can result in gene expression changes that promote a pro-inflammatory tumor microenvironment favorable of response to immune checkpoint blockade. It was known in the art cancer and tumors can find ways to use these checkpoints to avoid attack by the immune system and examples of "off-switches" are the proteins PD-1, PDL-1 and CTLA-4 as evidenced by Sorrentino (p1, line 14-22). The skilled artisan would have recognized that TNBC having PD-1+ immune infiltrates and high IFNG signature is a cancer having a surrounding microenvironment favorable to immune modulation or immunogenic cancer and positively associated with an improved clinical outcome of immunotherapy, and thus would be more responsive to the combination in view of Yeong et al. Thus, the skilled artisan would have been motivated to use the combination of the CDK4/6 inhibitor with ICD-inducing chemotherapy for treating TNBC having PD-1+ immune infiltrates and high IFNG signature, because such cancer was taught to have a surrounding microenvironment favorable to immune modulation and to be positively associated with an improved clinical outcome of immunotherapy as evidenced by Yeong et al. and would have reasonably expected that such cancer would be more likely responsive to the combination treatment for improving treatment prognosis and increasing disease-free survival (DFS) or overall survival of the patient.
As the new limitation, “the patient being eligible to receive ICD-inducing chemotherapy, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the combination of CDK4/6 inhibitor with ICD-inducing chemotherapy for those who are capable of inducing immune response by ICD-inducing chemotherapy because those who are sensitive to immune modulation and capable of inducing immune response would have favorable therapeutic response to the ICD-inducing chemotherapy in combination with the CDK4/6 inhibitor.
Response to Applicant’s argument
Responses are limited to Applicants' arguments relevant to either reiterated or newly applied rejections.
Applicants argued that stratifying patients by the immune status of the tumor microenvironment is surprisingly predictive of progression free survival (PFS) and overall survival (OS). Applicants further argued that surprisingly, the addition of trilaciclib to a gemcitabine/carboplatin chemotherapeutic regimen for the treatment of TNBC patients has a profoundly beneficial effect on PFS and OS for TNBC patients with a surrounding microenvironment that is favorable to immune modulation, for example as characterized by "high" IFN-γ signature score and/or "high" Expanded Immune Signature score in comparison to patients with a "high" IFN-γ Signature score and/or "high" Expanded Immune Signature score not receiving trilaciclib in their gemcitabine and carboplatin regimen.
In response, the examiner notes that it is applicant's burden to demonstrate unexpected results over the prior art. See MPEP 716.02, also 716.02 (a) - (g). Furthermore, the unexpected results should be demonstrated with evidence that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance. Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992). Moreover, evidence as to any unexpected benefits must be "clear and convincing" In re Lohr, 137 USPQ 548 (CCPA 1963), and be of a scope reasonably commensurate with the scope of the subject matter claimed, In re Linder, 173 USPQ 356 (CCPA 1972).
First, the alleged unexpected result of the claimed composition is not commensurate in scope with the claims. The claim 1 encompasses any cancer with any chemotherapy regimen to induce an immune-mediated response. However, the results are limited to the treatment of a specific cancer type, i.e., mTNBC having a "high" IFN-γ Signature score” or PD-L1 marker -with a specific chemotherapy, gemcitabine/carboplatin (GC). There are no results for other cancer types and other chemotherapy regimen. The disclosed results do not provide evidence of the alleged unexpected results for all the cancer types having different surrounding microenvironments that are favorable to immune modulation with different chemotherapeutic regimens encompassed by the claims.
Also, the improved effects by the addition of trilaciclib to a gemcitabine/carboplatin chemotherapeutic regimen for the treatment of TNBC patients would have been expected in view of the teachings of Sorrentino because Sorrentino discloses that the combination of the Compound I (Trilaciclib) with other chemotherapeutic agents resulted in improved overall survival compared to the chemotherapeutic agents alone (see Examples 1-4 and Tables 1-3). Also, it was known in the art that PD-1+ immune infiltrates, PD-L1 tumor cell expression and the expression of relevant genes including interferon gamma (IFNG) are positively associated with an improved clinical outcome of immunotherapy in TNBC as evidenced by Yeong et al. Thus, there is a reasonable expectation of improved effects in those TNBC patients having "high" IFN-γ signature score and/or "high" Expanded Immune Signature score. "Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof." In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967)
For the forgoing reasons, Applicant’s arguments have not been found to be persuasive.
Double Patenting Rejections
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1, 10-14, and 23-29 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-51 of US 11529352 in view of Yeong et al. (Journal for Immunotherapy of Cancer, 7:34, Fe. 6, 2019).
Although the conflicting claims are not identical, they are not patentably distinct from each other because the claims of ‘352 patent are drawn to a method of treating a subject having cancer such as TNBC comprising administering to the subject i) an effective amount of claimed CDK4/6 inhibitor (Compound I), ii) a chemotherapeutic agent, and a combination thereof, and iii) an immune checkpoint inhibitor, wherein the CDK4/6 inhibitor is only administered 4 hours or less prior to the administration of the chemotherapeutic agent and the chemotherapeutic agent can be selected from cisplatin, carboplatin gemcitabine, or a combination thereof.
The claims of the patent do not specifically recite that the patient’s TNBC is immunogenic with a high IFN-γ signature and the patient is eligible to receive an ICD-inducing chemotherapy.
It was known in the art that PD-1+ immune infiltrates, PD-L1 tumor cell expression and the expression of relevant genes including interferon gamma (IFNG) are positively associated with an improved clinical outcome of immunotherapy in TNBC as evidenced by Yeong et al. (abstract and conclusion). Yeong et al. teach that TNBC harbors relatively high numbers of tumor-infiltrating lymphocyte and expresses higher levels of PD-L1 compared to other breast cancer subtypes (p1, col2, last para-p2, col 1, para 1). Yeong et al. further teach that high expression of IFNG and IFN signaling genes was also associated with favorable disease-free survival (DFS) (abstract and Fig. 3h-i). TNBC having PD-1+ immune infiltrates and high expression of IFNG is a cancer having a surrounding microenvironment favorable to immune modulation or immunogenic cancer as claimed.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the combination treatment recited in the claims of the patent for patients who are more likely to respond to such combination by assessing known prognostic markers such as PD-1 and IFNG in the treatment of cancer such as TNBC because the claims of the patent recite the use of CDK4/6 inhibitor in combination with a chemotherapeutic agent such as carboplatin and gemcitabine and an immune checkpoint inhibitor such as PD-Ll inhibitor for treating TNBC. The skilled artisan would have recognized that TNBC having PD-1+ immune infiltrates and high expression of IFNG is a cancer having a surrounding microenvironment favorable to immune modulation or immunogenic cancer and positively associated with an improved clinical outcome of immunotherapy, and thus would be more responsive to the combination as evidenced by Yeong et al. Thus, the skilled artisan would have been motivated to use the combination for patients who are determined to be more likely responsive to it for improving treatment prognosis and increasing disease-free survival (DFS).
Response to Applicant’s arguments
Applicants argued that the claims of the '352 patent in view of Young fail to teach the stratification of patients based on their immune status or IFN-γ signature, or using the immune status of the patient's cancer/tumor microenvironment to inform whether trilaciclib administration prior to the administration of ICD-inducing chemotherapy will improve overall survival and/or progression free survival.
In response, the claims of ‘352 patent are drawn to a method of treating the same cancer (e.g., TNBC) with the same combination as claimed, wherein TNBC was taught to harbor relatively high numbers of tumor-infiltrating lymphocyte and expresses higher levels of PD-L1 compared to other breast cancer subtypes as evidenced by Yeong et al. (p1, col2, last para-p2, col 1, para 1). Also, Yeong et al. teach that PD-1+ immune infiltrates, PD-L1 tumor cell expression and the expression of relevant genes including interferon gamma (IFNG) are positively associated with an improved clinical outcome of immunotherapy in TNBC and high expression of IFNG and IFN signaling genes was also associated with favorable disease-free survival (DFS). In view of the teachings of Yeong et al., the skilled artisan would have recognized that TNBC having PD-1+ immune infiltrates and high expression of IFNG has a surrounding microenvironment favorable to immune modulation and is positively associated with an improved clinical outcome of immunotherapy and thus would be more responsive to the combination of the ‘352 patent. Thus, the skilled artisan would have been motivated to use the combination treatment recited in the claims of the patent in the treatment of cancer such as TNBC having known prognostic markers such as PD-1 and IFNG on the reasonable expectation that such cancer would be more likely to respond to such combination. And, the claimed intended result of improvement in overall survival and/or progression free survival would flow naturally from following the suggestion of the patent.
For the forgoing reasons, Applicant’s arguments have not been found to be persuasive.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
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/BONG-SOOK BAEK/Primary Examiner, Art Unit 1611
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