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 .
This action is in response to the papers filed on 12/16/2024. Claims 1-20 are
currently pending.
Claims 1-20 are examined on their merits to which the following grounds of
rejection are applicable. Claim 1 and 20 are independent claims.
Priority
This Application claims benefit of foreign filed CHINA 202311287919.9. Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d) to CHINA 202311287919.9 filed on 10/07/2023. However, a certified untranslated copy has not been provided.
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C.
119(a)-(d) prior to declaration of an interference, a certified English translation of the
foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e). Failure to provide a certified translation may result in no benefit being
accorded.
Thus, the earliest possible priority for the instant application is 10/07/2023.
Claim Objections
Claim 6 is objected to because abbreviations such as RECIST should be spelled out at the first encounter in the claims. Appropriate correction is required.
Claim 8 is objected to because abbreviations such as NK should be spelled out at the first encounter in the claims. Appropriate correction is required
Claim 15 is objected to because abbreviations such as AFP should be spelled out at the first encounter in the claims. Appropriate correction is required.
Claim 15 is objected to because the term “GPC3-CAR-T cell” is missing the indefinite article “a” preceding the noun. Appropriate correction is 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.
Claim 1-20 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 1 recites “therapeutically effective amount” in line 3. It is unclear what constitutes being a “therapeutically effective amount” as the specification does not disclose a definition for “therapeutically effective amount”. Appropriate correction is required. Claims 2-19 inherit these deficiencies insofar as they depend on claim 1.
It is noted that the phrase “local treatment” is defined at para 0228 of the US PG Publication US 20250114438 A1 Specification as the method for treating the local part of the tumor, including tumor surgical treatment, interventional treatment (for example, radiotherapy, endoscopic treatment, high-intensity focused ultrasound treatment).
Claims 2, 3, 6-10, 15, and 16 are indefinite for the recitation of “preferably”, more preferably” and “most preferably” because a broad range or limitation is together with a narrow range of limitation that falls within the broad range or limitation (in the same claim) is considered indefinite since the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. Appropriate action is required. Claim 12 inherit these deficiencies insofar as it depends on claim 6.
Claim 4 recites the term “and/or” in line 22. It is unclear what the metes and bounds of this term, as “and” could be interpreted to include only administration when no tumor recurrence is detected or both no tumor recurrence and metastasis is detected, or, “or” would imply that the detection types are in the alternative. Appropriate correction is required. Claims 11 is included in the rejection as it directly or indirectly depends on claim 1.
Claim 5 recites “the tumor antigen”. There is not proper antecedent bases in the claim or parent claim for the recitation of “the tumor antigen”. As such the metes and bound of the claim are indefinite.
Claim 6 recites “the tumor marker”. There is not proper antecedent bases in the claim or parent claim for the recitation of “the tumor marker”. As such the metes and bound of the claim are indefinite.
Claim 7 recites the term “and/or” in line 15. It is unclear what the metes and bounds of this term, as “and” could be interpreted to include only CAR or both CAR and recombinant TCR, or, “or” would imply that the receptor types are in the alternative. Appropriate correction is required.
Claim 16 recites the term “and/or” in line 22. It is unclear what the metes and bounds of this term, as “and” could be interpreted to include only administration when no tumor recurrence is detected or both no tumor recurrence and metastasis is detected, or, “or” would imply that the detection types are in the alternative. Appropriate correction is required.
Claim 6 recites “the immune cell therapy is administered if the tumor marker level is detected to be higher than the upper limit of the normal range or higher than the baseline level, or the tumor marker level is detected to be progressively increased”. It is unclear what constitutes “higher than the upper limit of the normal range or higher than baseline” and “progressively increased”. The specification does not define the metes and bounds of such ranges. Appropriate correction is required.
Claim 11 recites “the imaging detection”. There is not proper antecedent bases in the claim or parent claim for the recitation of “the imaging detection”. Claim 4 recites “imaging technology”. As such the metes and bound of the claim are indefinite.
Claim 12 recites “the solid tumor marker”. There is not proper antecedent bases in the claim or parent claim for the recitation of “the solid tumor marker”. As such the metes and bound of the claim are indefinite.
Claim 13 recites “the tumor antigen”. There is not proper antecedent bases in the claim or parent claim for the recitation of “the tumor antigen”. As such the metes and bound of the claim are indefinite.
Claim 15 recites “is administered by intravenous infusion if the AFP level in peripheral blood is detected to be higher than the upper limit of the normal range or higher than the baseline level, or the AFP level is progressively increased”. It is unclear what constitutes “higher than the upper limit of the normal range or higher than baseline” and “progressively increased”. The specification does not define the metes and bounds of such ranges. Appropriate correction is required.
Claim 16 recites “is administered by intravenous infusion if the CA19-9 level in peripheral blood is detected to be higher than the upper limit of the normal range or higher than the baseline level, or the CA19-9 level is progressively increased”. It is unclear what constitutes “higher than the upper limit of the normal range or higher than baseline” and “progressively increased”. The specification does not define the metes and bounds of such ranges. Appropriate correction is required.
Claim 19 recites “the subject has a high risk of cancer recurrence”. It is unclear what constitutes as “high” as “high” is a relative term. Appropriate correction is required.
Claim 20 recites “the tumor antigen”. There is not proper antecedent bases in the claim. As such the metes and bound of the claim are indefinite.
Claim Rejections - 35 USC § 112 – Scope of Enablement
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.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
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 of carrying out his invention.
Claim 1-20 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for:
An adjuvant treatment method comprising administering to subject in need thereof a GPC3-CAR-T cell or CLDN18.2-CAR-T cell therapy, wherein the administration is systemic after radical resection and microwave treatment of liver and pancreatic cancers, respectively, and further comprising a pretreatment of fludarabine, cyclophosphamide, and albumin-bound paclitaxel,
does not reasonably provide enablement for:
any adjuvant treatment method, comprising administering any adjuvant treatment to a subject with any solid tumor after receiving any local treatment; wherein the adjuvant treatment comprises: administering a therapeutically effective amount of any immune cell therapy comprising any chimeric receptor to the subject by intravenous infusion to any subject and further comprising any pretreatment.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected to make or use the invention commensurate in scope with these claims.
The factors to be considered in determining whether undue experimentation is
required are summarized in In re Wands, 858 F.2d 731, 737, 8 U.S.P.Q.2d 1400, 1404 (Fed. Cir. 1988) (a) the breadth of the claims; (b) the nature of the invention; (c) the
state of the prior art; (d) the level of one of ordinary skill; (e) the level of predictability in
the art; (f) the amount of direction provided by the inventor; (g) the existence of working
examples; and (h) the quantity of experimentation needed to make or use the invention
based on the content of the disclosure.
While all of these factors are considered, a sufficient number are discussed below so as to create a prima facie case.
the breadth of the claims; the nature of the invention:
Claim 1 is directed to an adjuvant treatment method, comprising administering the adjuvant treatment to a subject with a solid tumor after receiving local treatment; wherein the adjuvant treatment comprises: administering a therapeutically effective amount of immune cell therapy comprising a chimeric receptor to the subject by intravenous infusion. Claim 2 further limits claim 1 to a local treatment that reduces or eliminates tumor burden, claim 7 further limits wherein the chimeric receptor comprises a CAR and/or TCR, claim 8 further limits claim 1 wherein the immune cell is a T cell, a NK cell, a NKT cell, a human embryonic stem cell or a pluripotent stem cell. Claim 9 further limits to administering the immune cell therapy once, twice, or more than three times, claim 14 limits claim 1 wherein the solid tumor comprises a species listed. Claim 15 and 16 further limit claim 1 such that the treatment is for GPC3-positive solid tumors and CLDN18.2-positive solid tumors, respectively. Claims 17 and 18 further limit claim 1 wherein the chimeric receptor comprises a specific sequence set forth in a species of listed SEQ ID NOs. Claim 20 is an independent claim also directed to an adjuvant treatment method, comprising administering the adjuvant treatment to a subject with a solid tumor after radical surgery for the tumor; wherein the adjuvant treatment comprises: administering a therapeutically effective amount of immune cell therapy comprising a chimeric receptor to the subject by intravenous infusion, and the chimeric receptor binds to the tumor antigen expressed by the solid tumor.
the amount of direction provided by the inventor; the existence of working
examples:
As recited above, claim 1 and 20 are broadly but reasonably interpreted as an adjuvant treatment method, comprising administering the adjuvant treatment to a subject with a solid tumor after local treatment or radical surgery for the tumor; wherein the adjuvant treatment comprises: administering a therapeutically effective amount of immune cell therapy comprising a chimeric receptor to the subject by intravenous infusion, and the chimeric receptor binds to the tumor antigen expressed by the solid tumor.
The specification does not provide support for the genus of adjuvant treatments for the genus of solid tumors after receiving any type of local treatment wherein the treatment is administering any immune cell therapies via intravenous injection.
The specification only discloses an adjuvant treatment method comprising administering to a human subject either a GPC3-CAR-T cell or a CLDN18.2-CAR-T cell therapy:
Example 4, page 78: GPC3-CAR-T cell intravenously after microwave ablation of liver cancer and, prior to the GPC3-CAR-T cell therapy, detecting elevated AFP and administering a pretreatment of cyclophosphamide (Figure 1-2).
Example 5, page 79: GPC3-CAR-T cell intravenously after microwave ablation and surgical resection of liver cancer and, prior to the GPC3-CAR-T cell therapy, detecting elevated AFP and administering a pretreatment of cyclophosphamide
Example 6, page 80: GPC3-CAR-T cell intravenously after surgical resection of liver cancer and, prior to the GPC3-CAR-T cell therapy, and administering a pretreatment of cyclophosphamide and fludarabine
Example 7, page 81: CLDN18.2-CAR-T cell intravenously after surgical resection of pancreatic cancer and, prior to the CLDN18.2-CAR-T cell therapy, and administering a pretreatment of cyclophosphamide and fludarabine
Example 8, page 81-82: CLDN18.2-CAR-T cell intravenously after surgical resection of pancreatic cancer and, prior to the CLDN18.2-CAR-T cell therapy, and administering a pretreatment with fludarabine, cyclophosphamide, and albumin-bound paclitaxel in a human subject
Therefore, the specification only provides details for an intravenously administered adjuvant CAR-T cell therapy wherein the CAR is specific to GPC3 or CLDN18.2 and the local treatment prior to administration is radical surgery or microwave ablation and the treatment is preceded by a pretreatment of fludarabine, cyclophosphamide, and albumin-bound paclitaxel in a human subject.
the state of the prior art; the level of predictability in the art:
Although immune cell therapy for treatment of blood cancer has advanced to clinical application, Adjuvant treatment methods for treating solid tumors in subjects using an immune cell therapy comprising a chimeric receptor have been explored based on prior art, however remains an area of research as these technologies are still in their infancy stage of development.
Hou et al (Disease Markers, 2019, pages 1-11) teaches that the immune cell therapy CAR-T cell therapy has mixed results when used to treat solid tumors. Since solid tumors form differently than hematological tumors, certain obstacles must be considered when transferring CAR-T cell therapy, since, for example, tumor cells could form several discrete foci where T cells are obviously difficult to infiltrate and chemokines that are secreted by solid tumor cells are usually abnormal, which may lead to insufficient T cell recruitment (page 7, right col, para 2). In regards to specificity and ability of CAR-T cells to target solid tumors, Wang 2024 et al (Cancer Letters, 2024, pages 1-11) teaches tumor associated antigens, which are used to identify cells of interest for destruction by CAR-T cells, are heterogenous between tumors and normal tissue (i.e. not necessarily specific to tumors), hence CAR-T cells can be less effective in treating particular tumor cells of interest and thus can show off-target effects (page 2-3, 2.1. High heterogeneity of tumor-associated antigens). Similarly, Wang 2024 teaches that solid tumors exhibit a microenvironment that acts as a barrier to the immune system, therefore CAR-T cells are often incapable of infiltrating the solid tumors and have reduced activity due to adverse environmental conditions, further indicating unpredictability of success of CAR-T cell therapy for solid tumor treatment (Page 3, 2.2. Poor infiltration ability). Indeed, Wang 2025 et al (PNAS, 2025, pages 1-11) teaches the use of CAR-T cell therapy as an adjuvant treatment post-tumor resection surgery and further emphasizes that the aforementioned challenges of off-target effects, infiltration issues, and loss of activity remain present despite prior resection of tumors via surgery (pages 1 para 2-page 2 para 1).
Therefore, the prior art highlights the unpredictability in the use of an immune cell therapy, such as CAR-T cell therapy, as an adjuvant treatment method for solid tumors in subjects since it is not guaranteed that any CAR-T cell therapy against any solid tumor after any local treatment would elicit the desired effects.
the quantity of experimentation needed to make or use the invention based on the content of the disclosure:
The skilled artisan would be required to perform undue levels of experimentation
in order to practice the claimed invention. The instant specification does not reduce to
practice the claimed invention; the instant specification does not provide guidance on an adjuvant treatment method for any solid tumor after any local treatment and the treatment comprises administration of any immune cell therapy comprising any chimeric receptor intravenously. The specification only discloses the use of a CAR-T cell therapy as an adjuvant treatment method for specifically liver and pancreas cancer using a GPC3 CAR and CLDH18.2 CAR, respectively, and the method can comprise pretreatment with fludarabine, cyclophosphamide, and albumin-bound paclitaxel in a human subject. Moreover, the prior art highlights the unpredictability of using CAR-T cell therapy as a treatment, including as an adjuvant treatment, since many biological factors contribute to the variability in success.
Thus, the skilled artisan would be forced to 1) determine which solid tumor to treat 2) which immune cell therapy to use and in conjunction with what chimeric receptor and 3) determine if that immune cell therapy with the chimeric receptor is capable of being an adjuvant treatment against solid tumors in a subject.
the level of one of ordinary skill:
The level of one of ordinary skill is a PhD holder.
Conclusion:
When all of the Wands factors are considered together, they establish a prima
facie case that the specification is not enabling for the claims. The Specification only
provides details for an adjuvant treatment method comprising administering GPC3-CAR-T cell or CLDN18.2-CAR-T cell therapy intravenously after radical resection or microwave treatment of liver and pancreatic cancer, respectively, in a human subject, and further comprising a pretreatment of fludarabine, cyclophosphamide, and albumin-bound paclitaxel.
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)(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.
Claim(s) 1-3, 5, 7-9, 13, 14, 19, and 20 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Novina et al (US 20200306376 A1) as evidenced by Wikipedia, (Radical surgery, page 1; downloaded July 15, 2026) .
Regarding claim 1, 2, 7, and 8, Novina teaches methods of treating cancer, including solid tumors, comprising administering to a subject in need thereof, a therapeutically effective amount of chimeric antigen receptor T (CAR-T) cells (para 0028, 0141) and can be intravenously injected (para 0147). Novina teaches that the methods of the invention may also be used as an adjuvant treatment, e.g., to inhibit reoccurrence of cancer in patients with no currently detectable disease or after surgical removal of tumor (para 0145). Hence, Novina anticipates an adjuvant treatment method, comprising administering the adjuvant treatment to a subject with a solid tumor after receiving local treatment; wherein the adjuvant treatment comprises: administering a therapeutically effective amount of immune cell therapy comprising a chimeric receptor to the subject by intravenous infusion (claim 1), wherein the local treatment reduces or eliminates tumor burden; preferably, wherein the local treatment comprises surgical treatment (claim 2), wherein the chimeric receptor comprises a chimeric antigen receptor (CAR) (claim 7), and wherein the immune cell comprises a T cell (claim 8).
Regarding claim 3, the teachings of Novina anticipate claim 1. Moreover, Novina teaches the therapeutic methods of the invention may also be “second-line” in the sense that they are administered to patients who have undergone at least one prior anti-cancer treatment regimen, e.g., chemotherapy or any combination thereof either alone or in combination with other treatments (para 0145). Hence, Novina anticipates wherein the immune cell therapy is administered after the local treatment combined with other adjuvant treatment; and the other adjuvant treatment does not comprise the immune cell therapy and preferably, wherein the other adjuvant treatment comprises chemotherapy.
Regarding claim 5, the teachings of Novina anticipate claim 1. Moreover, Novina teaches invention comprises targeting moieties which have binding specific for tumor associated antigens (TAAs) where in the CAR-T cell binds to a small molecule which is bound to a TAA (para 0048-0050). Hence, Novina anticipates wherein the chimeric receptor binds to the tumor antigen expressed by the solid tumor.
Regarding claim 9, the teachings of Novina anticipate claim 1. Moreover, Novina teaches the CAR-T cells are administered once (para 0030), hence Novina anticipates comprising administering the immune cell therapy once.
Regarding claim 13, the teachings of Novina anticipate claim 1. Moreover, Novina teaches the solid tumor comprises TAAs to which the targeting moiety may be directed including AFP, IL13Rα or CEA, hence Novina anticipates wherein the tumor antigen expressed by the solid tumor comprises AFP, IL13Rα or CEA.
Regarding claim 14, the teachings of Novina anticipate claim 1. Moreover, Novina teaches examples of cancers characterized by solid tumors which may be treated with the invention include breast, colorectal, colon, esophageal, liver, among other, hence Novina anticipates wherein the solid tumor comprises: liver cancer, esophageal cancer, colon cancer, rectal cancer, breast cancer, among others.
Regarding claim 19, the teachings of Novina anticipate claim 1. Moreover, Novina teaches cancers to be treated include recurrent or refractory tumors. Recurrent tumors encompass tumors that appear to be inhibited by treatment with such agents, but which recur up to five years, or even up to ten years, or longer, after treatment is discontinued (para 0144).
Regarding independent claim 20, Novina teaches methods of treating cancer, including solid tumors, comprising administering to a subject in need thereof, a therapeutically effective amount of chimeric antigen receptor T (CAR-T) cells (para 0028, 0141) and can be intravenously injected (para 0147) such that the CAR on the CAR-T cell binds to a pro-antigen which is bound to a tumor associated antigen. Novina teaches that the methods of the invention may also be used as an adjuvant treatment, e.g., to inhibit reoccurrence of cancer in patients with no currently detectable disease or after surgical removal of tumor (para 0145). Hence, Novina anticipates an adjuvant treatment method, comprising administering the adjuvant treatment to a subject with a solid tumor after surgery for the tumor wherein the adjuvant treatment comprises: administering a therapeutically effective amount of immune cell therapy comprising a chimeric receptor to the subject by intravenous infusion, and the chimeric receptor binds to the tumor antigen expressed by the solid tumor.
While Novina does not explicitly state the surgery is a radical surgery, Novina recites that the surgery performed in conjunction with the invention is curative surgery which includes resection in which all or part of cancerous tissue is physically removed, excised, and/or destroyed (para 0172). Novina recites that the present invention may be used in conjunction with removal of superficial cancers, precancers, or incidental amounts of normal tissue (para 0172). Radical surgery is defined as surgery intended to remove both a tumor and any metastases of it (Wikipedia, Radical surgery, page 1), hence Novina anticipates claim 20.
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.
Claim(s) 1, 4, 6, 10-12, and 15-18 are rejected under 35 U.S.C. 103 as being unpatentable over Novina et al (US 20200306376 A1) and further in view of Powles et al (Nature, 2021, pages 432-456), Liu et al (cancers, 2022, pages 1-17), Kim et al (Journal of Surgical Oncology, 2011, pages 585-591), Wang et al (US 20190046659 A1; hereinafter “Wang 2019”, and Wang et al (US 20220184126 A1; hereinafter “Wang 2022”), as evidenced by Wikipedia (Radial Surgery, page 1, downloaded July 15, 2026) and Blaj (Radiology Modalities, pages 1-15, downloaded July 16, 2026).
The applied Wang 2019 reference has a common inventor with the instant application. Based upon the earlier publication date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(1). The publication dated for Wang 2019 is 14 February 2019. The earliest effective filing date of the instant application is October 7, 2023.
Therefore rejection under 35 U.S.C. 103 CANNOT be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(c) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02. Because the reference qualifies as prior art under 102(a)(1), the provisions of MPEP 717.02 do not apply.
Regarding claim 1, Novina teaches methods of treating cancer, including solid tumors, comprising administering to a subject in need thereof, a therapeutically effective amount of chimeric antigen receptor T (CAR-T) cells (para 0028, 0141) and can be intravenously injected (para 0147). Novina teaches that the methods of the invention may also be used as an adjuvant treatment, e.g., to inhibit reoccurrence of cancer in patients with no currently detectable disease or after surgical removal of tumor (para 0145).
Regarding claim 4, the teachings of Novina teach claim 1.
The teachings of Novina do not teach wherein after the local treatment or the local treatment combined with the other adjuvant treatment, the immune cell therapy is administered when no tumor recurrence and/or metastasis is detected.
However, one of ordinary skill in the art would have considered the teachings of
Powles as this reference is analogous prior art pertaining to administering adjuvant immunotherapies.
Powles teaches administration of adjuvant atezolizumab upon evaluation of circulating tumour DNA (ctDNA) presence in urothelial cancer patients who may be at risk of metastatic relapse (abstract, page 432). Powles teaches that patients were required to have undergone surgical resection (cystectomy or nephroureterectomy) with
lymph node dissection, with no evidence of residual disease or metastasis as confirmed by negative postoperative radiological imaging (methods, left col, para 1, page 438) prior to the adjuvant atezolizumab treatment, and after the adjuvant atezolizumab treatment, those patients with ctDNA showed higher probability of disease-free survival compared to no treatment (Figure 1; abstract, page 1).
It would have been prima facie obvious to one of ordinary skill, in the art at the time of the effective filing date, to modify the teachings of an adjuvant treatment method comprising administering an immune cell therapy as taught by Novina to specifically administer the adjuvant treatment when there is no tumor recurrence, metastasis or no enlargement is detected by imaging technology since Powles teaches that an adjuvant treatment where there is no evidence of residual disease or metastasis can increase the probability of disease-free survival in patents with ctDNA. One would be motivated to do so to have an adjuvant treatment method for patients with detectable disease in order to increase their chances of disease-free survival. As use of adjuvant treatment methods and detection of disease state are known in the art, one would have a reasonable expectation of success.
Regarding claim 6, the teachings of Novina teach claim 1.
The teachings of Novina do not teach wherein after the local treatment or the local treatment combined with the other adjuvant treatment, the immune cell therapy is administered if after the local treatment or the local treatment combined with the other adjuvant treatment, the immune cell therapy is administered if circulating tumor DNA (ctDNA) are detected in peripheral blood.
However, one of ordinary skill in the art would have considered the teachings of
Powles as this reference is analogous prior art pertaining to administering adjuvant immunotherapies based on ctDNA detection.
Powles teaches administration of adjuvant atezolizumab upon evaluation of circulating tumour DNA (ctDNA) in urothelial cancer patients who may be at risk of metastatic relapse (abstract, page 432). Powles teaches that detection of ctDNA shortly after surgical resection may enable early identification of patients with molecular residual disease and that patients who were positive for ctDNA and treated with the adjuvant atezolizumab showed improved probability of disease-free survival compared to observation (i.e no treatment) (page 433, left col, para 1; Figure 1; abstract, page 432).
It would have been prima facie obvious to one of ordinary skill, in the art at the time of the effective filing date, to modify the teachings of an adjuvant treatment method comprising administering an immune cell therapy as taught by Novina to specifically administer the adjuvant treatment when there is circulating tumor DNA (ctDNA) detected in the patient since Powles teaches that administration of the adjuvant treatment in patients with detectable ctDNA led to higher probability of disease-free survival compared to no treatment. One would be motivated to do so to have an adjuvant treatment method for patients with detectable disease in order to increase their chances of disease-free survival. As use of adjuvant treatment methods and detection of disease state are known in the art, one would have a reasonable expectation of success.
Regarding claim 10, the teachings of Novina teach claim 1.
Novina does not teach that pretreatment is administered about 1-12 days before each administration of the immune cell therapy.
However, one of ordinary skill in the art would have considered the teachings of
Liu as this reference is analogous prior art pertaining to pre-treatment to increase the efficacy of CAR-T cell therapies.
Liu teaches that when CAR-T cells are infused in the blood, they require a suitable immunomodulatory environment for T cell survival and proliferation, hence pre-treatment lymphodepletion with Cyclophosphamide (Cy) and fludarabine (Flu) prior to CAR T-cell infusion can help increase the efficacy of the CAR-T cell therapy (page 4, 2. Lymphodepletion Regimen, para 1). Liu teaches the lymphodepletion with Cy and/or Flu can occur 5, 4, or 3 days before the CAR-T cell infusion (page 4, 2. Lymphodepletion Regimen, para 2).
It would have been prima facie obvious to one of ordinary skill, in the art at the time of the effective filing date, to modify the teachings of an adjuvant treatment method comprising administering an immune cell therapy as taught by Novina to include a pre-treatment step before the administration of the CAR-T cell therapy as Liu teaches that pre-treatment with agents such as Cy and Flu can create a more favorable environment for T-cell proliferation and survival, thus increasing the efficacy of the CAR-T cell therapy/immune cell therapy. One would be motivated to combine the teachings to have an adjuvant method that is more effective at treating a subject due to pre-treatment before administration. As pre-treatment in immune cell therapy regimens is known in the art, one would have a reasonable expectation of success.
Regarding claim 11, the teachings of Novina and Powles render obvious claims 1 and 4. Moreover, Powles teaches that confirmation of residual disease or metastasis is confirmed by negative postoperative radiological imaging. The practitioner in the art would readily understand that radiological imaging comprises CT scan, MRI, X-ray examination as evidenced by Blaj (Radiology Modalities, pages 1-15).Regarding claim 12, the teachings of Novina and Powles render obvious claims 1 and 6.
The combined teachings Novina and Powles do not teach wherein the solid tumor marker comprises: ALK, AFP, B2M, Beta-hCG, BTA, C-kit/CD117, CA15-3, CA19-9, CA724, CA-125, CA 27.29, Calcitonin, CEA, CD19, CD20, CD22, CD25, CD30, CD33, CgA, DCP, ER/PR, 5-HIAA, PSA, SMRP, a squamous cell carcinoma (SCC) antigen, or a soluble fragment of cytokeratin 19 (CYFRA21-1).
However, one of ordinary skill in the art would have considered the teachings of
Kim as this reference is analogous prior art pertaining to tumor markers and their relationship with recurrence in gastric cancer.
Kim teaches that the tumor markers CEA, CA 19-9, and CA 72-4 can be easily measured by postoperative follow-up blood tests of gastric cancer patients and that the postoperative follow-up blood tests can promote prolonged survival and increased quality of life for patients by detecting recurrence early and aiding selection of the appropriate treatment (Page 588, Discussion, left col, para 1). Kim teaches the normal values of CEA, CA 19-9, and CA 72-4 were set at less than 7 ng/ml, 35 U/ml, and
4 U/ml, respectively (page 586, left col, para 2).
It would have been prima facie obvious to one of ordinary skill, in the art at the time of the effective filing date, to modify the teachings of an adjuvant treatment method comprising administering an immune cell therapy as taught by Novina and the teachings of Powles for using ctDNA as a marker for administering the immune cell therapy to instead use tumor markers such as CEA, CA 19-9, and CA 72- as Kim teaches that CEA, CA 19-9, and CA 72-4 can be used to determine recurrence of gastric cancer specifically when above normal levels, therefore one would be motivated to combine these teachings to arrive at the adjuvant method being administered when tumor marker levels are higher than normal.
Regarding claim 15, the teachings of Novina teach claim 1.
The teachings of Novina do not teach wherein the method is used to treat a subject with a GPC3-positive solid tumor, and after the local treatment or the local treatment combined with the other adjuvant treatment, GPC3-CAR-T cell is administered by intravenous infusion if no tumor recurrence and/or metastasis is detected by imaging technology.
However, one of ordinary skill in the art would have considered the teachings of
Wang 2019 as this reference is analogous prior art pertaining to an immunotherapy providing CAR-T cells with targeting abilities to GPC3-positive solid tumors.
Wang 2019 teaches GPC3 is highly detected in early stage of hepatocellular carcinoma and the detection rate is also increased with the development of liver cancer (para 0004). Wang 2019 teaches GPC3 is considered a candidate target for tumor immunotherapy in view of the high specific expression of GPC3 in tumors such as hepatocellular carcinoma and melanoma (para 0004). Wang 2019 teaches an antibody which targets GPC3-positive cells and the antibody can be used for the preparation of chimeric antigen receptor-modified immune cells wherein the immune cells include T lymphocyte, NK cell or NKT lymphocyte (i.e. CAR-T cells) (para 0007, 0038, and 0051).
It would have been prima facie obvious to one of ordinary skill, in the art at the time of the effective filing date, to modify the teachings of an adjuvant treatment method comprising administering an immune cell therapy as taught by Novina to specifically treat a subject with a GPC3-CAR-T cell therapy that can treat GPC3-positive solid tumors since Wang 2019 teaches an antibody against GPC3 that can be prepared for CAR-T cell therapy and that GPC3 can be detected to indicate tumor presence. One would be motivated to combine the teachings to arrive at an adjuvant method specifically for treating GPC3-postitive solid tumors and since GPC3-CAR-T cell therapies are known in the art, one would have a reasonable expectation of success.
Regarding claim 16, the teachings of Novina teach claim 1.
The teachings of Novina do not teach wherein the method is used to treat a subject with CLDN18.2-positive solid tumor, and after the local treatment or the local treatment combined with the other adjuvant treatment, CLDN18.2-CAR-T cell is administered by intravenous infusion if no tumor recurrence and/or metastasis is detected by imaging technology; preferably, wherein the CLDN18.2-positive solid tumor comprises: gastrointestinal tumor, gastric adenocarcinoma, gastroesophageal junction adenocarcinoma, gastric cancer, pancreatic cancer, gastroesophageal junction cancer, esophageal cancer, pancreatic ductal adenocarcinoma, or ovarian carcinoma; more preferably, wherein the method is used to treat a subject with CLDN18.2-positive gastric cancer or gastroesophageal junction tumor, and after the local treatment or the local treatment combined with the other adjuvant treatment, CLDN18.2-CAR-T cell is administered by intravenous infusion if no tumor recurrence and/or metastasis is detected by imaging technology; most preferably, wherein the method is used to treat a subject with CLDN18.2-positive pancreatic cancer, and after the local treatment or the local treatment combined with the other adjuvant treatment, CLDN18.2-CAR-T cell is administered by intravenous infusion if the CA19-9 level in peripheral blood is detected to be higher than the upper limit of the normal range or higher than the baseline level, or the CA19-9 level is progressively increased.
However, one of ordinary skill in the art would have considered the teachings of
Wang 2022 as this reference is analogous prior art pertaining to an immunotherapy providing CAR-T cells for treatment of diseases associated with the expression of CLDN12.2 such as cancer.
Wang 2022 teaches humanized anti-claudin18.2 (CLDN18.2) chimeric antigen receptors (CARs) and T cells engineered to express the CARs (CAR-T cells) (para 002). Wang 2022 teaches dysregulated expression of claudins are detected in many cancers and may contribute to tumorigenesis and cancer invasiveness and the expression of CLDN18.2 is elevated in pancreatic ductal adenocarcinomas, esophageal tumor, and bile duct adenocarcinomas and that CLDN18.2 is an ideal target for CAR-T cell therapies to treat and cure CLDN18.2-positive cancers (para 0006).
It would have been prima facie obvious to one of ordinary skill, in the art at the time of the effective filing date, to modify the teachings of an adjuvant treatment method comprising administering an immune cell therapy as taught by Novina to specifically treat a subject with a CLDN18.2-CAR-T cell therapy that can treat CLDN18.2-positive solid tumors since Wang 2022 teaches a CAR against CLDN18.2 that can be expressed in T cells, thus developing an immune cell therapy that can particularly treat CLDN18.2. One would be motivated to combine the teachings to arrive at an adjuvant method specifically for treating CLDN18.2-postitive solid tumors and since CLDN18.2-CAR-T cell therapies are known in the art, one would have a reasonable expectation of success.
Regarding claim 17, the teachings of Novina teach claim 1.
The teachings of Novina do not teach wherein the antigen binding unit of the chimeric receptor comprises a sequence having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, 47, 48, 49, 50, 62 or 63.
Wang 2019 teaches an amino acid sequence (SEQ ID NO: 4) for a P7D4 (i.e. also known as GPC3) chimeric antigen receptor binding region which has 100% sequence identity to SEQ ID NO: 1 of the instant application. See sequence alignment below.
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Qy: instant application SEQ ID NO: 1, Db: Wang 2019 SEQ ID NO: 4
Regarding claim 18, the teachings of Novina teach claim 1.
The teachings of Novina do not teach wherein the chimeric receptor comprises a sequence having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 28, 29, 30, 51, 52, 53, 54, 60 or 61.
Wang 2019 teaches an amino acid sequence (SEQ ID NO: 88) for the CAR-GPC3 of a T cell (Y035) which has 100% sequence identity to SEQ ID NO: 28 of the instant application. See sequence alignment below.
Qy: instant application SEQ ID NO: 28, Db: Wang 2019 SEQ ID NO:
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88
Provisional Rejection, Obviousness Type Double Patenting
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.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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/apply/applying-online/eterminal-disclaimer.
Claims 1-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 2, 6, and 12 of copending Application No. 18/573,685 as per claims filed on 03/06/2024, in view of Powles et al (Nature, 2021, pages 432-456). Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are obvious over the cited claims of Application No. 18/573,685.
The claims of co-pending application 18/573,685 are drawn to a method for treating a subject suffering from or suspected of suffering from a CLD 18 positive biliary tract tumor, comprising administrating cells that express exogenous receptors targeting CLD18 to the subject (claim 1) and wherein the CLD18 is CLD18.2 (i.e. CLDH18.2) (claim 2), the exogenous receptors can be a chimeric antigen receptor (CAR) (claim 6), and a pretreatment is performed 1-8 days before administrating the cell therapy product (claim 12).
The instant application differs from claims 1, 2, 6, and 12 by requiring the treatment to be administered after receiving a local treatment. The instant claims are also broadly directed to a genus of solid tumors.
In relation to the claimed solid tumor treatment of claims 1 and 20, the claims of Application No. 18/573,685 anticipate the instant genus. In relation to the recitation of “receiving local treatment” in claim 1 of the invention, one of ordinary skill in the art would have considered the teachings of Powles.
However, at the time the invention was made, Powles teaches administration of adjuvant atezolizumab upon evaluation of circulating tumour DNA (ctDNA) in urothelial cancer patients who may be at risk of metastatic relapse (abstract, page 432). Powles teaches that patients were required to have undergone surgical resection (cystectomy or nephroureterectomy) with lymph node dissection, with no evidence of residual disease or metastasis as confirmed by negative postoperative radiological imaging (methods, left col, para 1, page 438) prior to the adjuvant atezolizumab treatment, and after the adjuvant atezolizumab treatment, those patients with prior ctDNA showed higher probability of disease-free survival compared to no treatment (Figure 1; abstract, page 1).
Therefore, in view of the teachings of Powles for administering an adjuvant treatment after surgical tumor resection (i.e. a local treatment), it would have been prima facie obvious to one of ordinary skill, in the art at the time of the effective filing date, to modify the instantly claimed methods to be administered after a local treatment since Powles teaches that an adjuvant treatment given after surgical resection can increase the probability of disease-free survival in patients.
Conclusion
No claims are allowed.
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/JULIANA IRENE CANDELARIA/ Examiner, Art Unit 1634
/MARIA G LEAVITT/ Supervisory Patent Examiner, Art Unit 1634
Prosecution Insights