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
Claim Status
Applicant's amendment filed on December 15, 2025 has been received and entered.
Claims 1, 4-7, and 9 have been amended.
Claims 10-18 have been canceled.
Claims 21-26 have been added.
Claims 1-9 and 19-26 are pending and under consideration.
Priority
In view of Applicant’s amendment filed December 15, 2025, the benefit of priority has been perfected as follows:
This application is a continuation-in-part of U.S. Application No. 17/781,966 filed June 2, 2022, which claims the benefit of U.S. Provisional Application No. 63/322,449 filed March 22, 2022. U.S. Application No. 17/781,966 is a 371 of PCT/IL2020/051244 filed December 2, 2020, which claims the benefit of U.S. Provisional Application No. 62/942,276 filed on December 2, 2019.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on December 15, 2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Specification
In view of the Applicant’s amendment, the previous objection to the specification is withdrawn.
Claim Objections
In view of the Applicant’s amendment, the previous objections to the claims are withdrawn.
Claim Rejections
In view of the Applicant’s claim amendments, the previous grounds of rejection are withdrawn. The following are new grounds of rejection necessitated by Applicant’s claim amendments. Applicant’s arguments relevant to the new grounds of rejection will be addressed below.
Claim Rejections - 35 USC § 112(a) - 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.
Claims 1 and 31 are rejected under 35 U.S.C. 112(a) because the specification, while being enabling for:
A method of treating a subject suffering from cancer or at risk of cancer relapse comprising measuring soluble CD28 (sCD28) levels before administering an anti-PD-1/PD-L1 immunotherapy, and measuring sCD28 at least once after administering the anti-PD-1/PD-L1 immunotherapy, wherein a different immunotherapy is administered if the sCD28 levels are above a predetermined threshold,
does not reasonable provide enablement for:
A method of treating a subject suffering from cancer or at risk of cancer relapse comprising measuring soluble CD28 (sCD28) levels before administering an anti-PD-1/PD-L1 immunotherapy, and measuring sCD28 at least once after administering the anti-PD-1/PD-L1 immunotherapy, wherein an increased dose of the initial anti-PD-1/PD-L1 immunotherapy, a CTLA-4 checkpoint inhibitor, a CAR-T based therapy, a CAR-NK based therapy, or a cancer vaccine is administered if the sCD28 levels are above a predetermined threshold.
The specification disclosure is insufficient to enable one skilled in the art to practice the invention as claimed without an undue amount of experimentation. Undue experimentation must be considered in light of factors including: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill in the art, the level of predictability of the art, the amount of direction provided by the inventor, the existence of working examples, and the quantity of experimentation needed to make or use the invention, in re Wands, 858 F.2d at 737, 8 USPQ2d at 1404 (Fed. Cir. 1988).
“The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art.” In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The “amount of guidance or direction” refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling (MPEP 2164.03). The MPEP further states that physiological activity can be considered inherently unpredictable.
The instant claims are directed to a method of treating a subject suffering from cancer or at risk of cancer relapse comprising measuring soluble CD28 (sCD28) levels before administering an anti-PD-1/PD-L1 immunotherapy, and measuring sCD28 at least once after administering the anti-PD-1/PD-L1 immunotherapy, wherein a different immunotherapy is administered if the sCD28 levels are above a predetermined threshold. Claims 22-26 recite that the alternative anticancer therapy is a CTLA-4 inhibitor, CAR-T therapy, CAR-NK therapy, or a cancer vaccine.
Thus, given the unpredictability of the art and the breadth of the claims, the instant specification must provide a sufficient an enabling disclosure commensurate in scope with the instant claims. The specification provides guidance for using an alternative cancer therapy to reduce sCD28 levels [074] by treating with a matrix metalloprotease inhibitor (MMP) or anti-CD28 VHH antibodies that bind CD28. However, there are no examples of treating cancer with a CTLA-4 inhibitor, CAR-T therapy, CAR-NK therapy that reduce elevated levels of sCD28.
The specification does not provide any guidance or examples for treating cancer in patients that have elevated sCD28 levels after anti-PD-1/PD-L1 therapy with alternative anticancer therapies as broadly encompassed by the instant claims. Thus, given the unpredictability of the art and the lack of guidance provided by the instant specification, it would require undue experimentation to practice the method as broadly claimed.
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.
Claim 6 is 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 6 recites “wherein said administering is administering an increased dose of said PD-1/PD-L1 immunotherapy to said subject.”, however, it is unclear when an increased dose is administered. Is an increased dose administered after the first time point? Or is the increased dose administered after the second time point (i.e., further administrating)? The specification provides no clarification or examples wherein a dose of PD-1/PD-L1 immunotherapy is increased, therefore the claim is ambiguous. Acceptable edits include “wherein said further administering is administering an increased dose of said PD-1/PD-L1 immunotherapy to said subject.”
Appropriate correction is required.
Claim Rejections - 35 USC § 103
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 1-9 and 19-26 are rejected under 35 U.S.C. 103 as being unpatentable over Hakim et al. (WO 2019/175885; cited IDS 3/22/2023) (“Hakim”).
The instant claims are drawn to a method of treating a subject suffering from cancer or at risk of cancer relapse comprising measuring soluble CD28 (sCD28) levels before administering an anti-PD-1/PD-L1 immunotherapy, and measuring sCD28 at least once after administering the anti-PD-1/PD-L1 immunotherapy, wherein a different immunotherapy, or an increased dose of the same anti-PD-1/PD-L1 immunotherapy, is administered if the sCD28 levels are above a predetermined threshold.
Hakim teaches methods of treating cancer and/or preventing cancer comprising decreasing soluble CD28 (sCD28) levels in a subject in need thereof, wherein decreasing sCD28 levels improves PD-1 and/or PDL-1 based immunotherapy [009-010].
Hakim teaches a large number of cancer patients have elevated sCD28 levels in their blood stream and can be used a biomarker. Hakim found that sCD28 inhibits PD-1 PDL-1 based immunotherapy, providing a possible rationale as to why not all patients respond to PD-1 based immunotherapy or immunotherapy, and those that do often relapse [007, 070, 0276].
Hakim teaches the subject has melanoma, head and neck cancer, non-small cell lung cancer, or kidney cancer, and is a non-responder to PD-1/PD-L1 therapy and the subject's blood comprises elevated levels of sCD28 that are at least 5% above those of healthy subjects or a predetermined threshold [0180, 0187]. Subjects include those at risk for developing cancer [0198]. The method further comprises administering another immunotherapy such is a CTLA-4 checkpoint inhibitor, CAR-T based therapy, a CAR-NK based therapy, or a cancer vaccine [0182-0183, 0186].
Specifically, Hakim teaches determining sCD28 levels in a sample obtained from a subject, wherein an elevated sCD28 level above 5 ng/mL indicates the subject is unsuitable to be treated anti-PD-1 and/or PD-L1 immunotherapy. Also taught are methods for making an unsuitable subject suitable to receive anti-PD-1 and/or PD-L1 immunotherapy by decreasing sCD28 levels in the subject [0191-0192].
Hakim also teaches that reducing sCD28 levels can improve CD80 and/or CD86 based immunotherapy, wherein the method comprises measuring sCD28 levels in the subject and increasing the dose of CD80 and/or CD86 based immunotherapy when sCD28 levels are above 5 ng/mL [0193].
The teachings of Hakim differ from those of the instant invention in that even though elevated levels of sCD28 that leads to anti-PD-1 resistance during cancer treatment which can be overcome by treating with another immunotherapy that reduces sCD28 levels is taught, Hakim does not explicitly teach sCD28 levels are measured prior to anti-PD-1/PD-L1 immunotherapy or 7 days post anti-PD-1/PD-L1 immunotherapy, increasing the dose of the initial anti-PD-1/PD-L1 immunotherapy, or that the method is for the treatment of patients with imminent cancer relapse. It would have been obvious to one of ordinary skill in the art at the time of the instant invention to measure sCD28 levels in cancer patients undergoing anti-PD-1 therapy and administer an additional immunotherapy if sCD28 levels rise above the threshold limit given that Hakim teaches sCD28 is a potent inhibitor of anti-PD-1 therapy [0273]. The instant specification defines “imminent cancer relapse” as relapse within the next 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or 20 weeks. Hakim teaches the method can be used to treat those at risk for cancer, which encompasses subjects with “imminent cancer relapse”.
Hakim teaches the threshold for sCD28 levels is 5 ng/mL versus 1 ng/mL as recited in the instant claims and is silent regarding when samples are taken post-initial anti-PD-1/PD-L1 immunotherapy.
The Court has stated that generally such differences amount to mere optimization and will not support patentability unless there is evidence indicating the claimed feature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” MPEP 2144 sets forth Applicant' s burden for rebuttal of a prima facie case of obviousness based upon routine optimization. Applicant must provide either a showing that the particular amount or range recited within the claims is critical; and/or a showing that the prior art reference teaches away from the claimed amount. 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.
Double Patenting
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.
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 1-9 and 19-26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6, and 10 of US Patent No. 12,139,534 in view of Hakim et al. (WO 2019/175885; cited IDS 3/22/2023) (“Hakim”).
Although the claims at issue are not identical, they are not patentably distinct from each other because the copending claims are drawn to improving PD-1/PD-L1 based therapy in subjects with cancer by reducing soluble CD28 (sCD28) levels, which reads on the instant invention.
The instant claims differ from the issued claims in that they do not explicitly teach monitoring sCD28 levels before and after anti-PD-1/PD-L1 therapy, when the second sample for sCD28 measurement is taken, or that patients are non-responders to PD-1/PD-L1 therapy or are in risk for imminent relapse.
The teachings of Hakim are set forth above.
It would have been obvious to one of ordinary skill in the art at the time of the instant invention to measure sCD28 levels in cancer patients undergoing anti-PD-1 therapy and administer an additional immunotherapy if sCD28 levels rise above the threshold limit given that Hakim teaches sCD28 is a potent inhibitor of anti-PD-1 therapy.
The instant specification defines “imminent cancer relapse” as relapse within the next 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or 20 weeks. Hakim teaches the method can be used to treat those at risk for cancer, which encompasses subjects with “imminent cancer relapse”.
Regarding when the second sample is taken, [T]he Court has stated that generally such differences amount to mere optimization and will not support patentability unless there is evidence indicating the claimed feature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” MPEP 2144 sets forth Applicant' s burden for rebuttal of a prima facie case of obviousness based upon routine optimization. Applicant must provide either a showing that the particular amount or range recited within the claims is critical; and/or a showing that the prior art reference teaches away from the claimed amount.
As such, the instant claimed invention is an obvious modification of the patented claims in view of Hakim.
Claims 1-9 and 19-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4, and 9 of copending Application No. 17/781,966 in view of Hakim et al. (WO 2019/175885; cited IDS 3/22/2023) (“Hakim”). Although the claims at issue are not identical, they are not patentably distinct from each other because The are coextensive in scope.
The instant claims are drawn to a method of treating a subject suffering from cancer or at risk of cancer relapse, the method comprising administering an anti-PD 1/PD-L1 immunotherapy to said subject, measuring soluble CD28 (sCD28) levels in said subject for least two time points wherein at least a first time point is before said administering and at least a second time point is after said administering, and further administering an agent that reduces sCD28 levels to a subject whose sCD28 levels increased from before administering to after administering by at least a predetermined threshold, thereby treating a subject suffering from cancer. Dependent claim 19 is drawn to a method of treating an imminent cancer relapse and said second time point is while said subject is responding to said immunotherapy.
The copending claims are drawn to a method of treating cancer or at risk for relapse in a subject in need thereof, the method comprising measuring soluble CD28 (sCD28) levels in said subject, wherein the subject is treated with an alternative anticancer therapy or an increased dose of an anti-PD-1/PD-L1 inhibitor if sCD28 levels increase above a predetermined threshold.
Therefore it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the instant invention that the claims of the copending application encompass the instant claims. The artisan would be motivated to modify the claims of the copending application as they broadly encompass the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant has argued that Hakim et al. (2020) is not a valid reference as it has a publication date that is later than the priority date of the instant application.
Applicant’s arguments with respect to the rejection of claims 1-9 and 19-26 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. 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 nonprovisional extension fee (37 CFR 1.17(a)) 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 mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MAUREEN DRISCOLL whose telephone number is (571) 270-0730. The examiner can normally be reached Monday through Friday.
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/MAUREEN VARINA DRISCOLL/ Examiner, Art Unit 1642
/DANIEL E KOLKER/Supervisory Patent Examiner, Art Unit 1645