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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on June 4, 2026 has been entered.
Claim Status
Claims 1 and 6 have been amended.
Claims 3-4 have been canceled.
Claims 10-18 were previously canceled.
Claim 27 has been added.
Claims 1-2, 5-9, and 19-27 are pending and under consideration.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. This application is a continuation-in-part of U.S. Application 17/781,966 filed June 2, 2022, which claims the benefit of U.S. Provisional Application No. 63/322,449 filed March 22, 2022, which is a 371 of PCT/IL2020/051244 filed December 2, 20020, which claims the benefit of U.S. Provisional Application No. 62/942,276 filed December 2, 2019.
However, Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosures of PCT/IL2020/051244 and Application No. 62/942,276 fail to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) for one or more claims of this application.
Claim 1 is drawn to a method of treating a subject suffering from cancer or at risk of cancer relapse, comprising administering an anti-PD-1/PD-L1 immunotherapy and measuring soluble CD28 (sCD28) levels before and after anti-PD-1/PD-L1 immunotherapy administration, wherein the subject is diagnosed as a non-responder to anti-PD-1/PD-L1 immunotherapy if their sCD28 levels increase from before administering to after administering by at least a predetermined threshold.
Claims 5 and 7 recite the predetermined threshold is an increase of at least 1 ng/mL sCD28.
PCT/IL2020/051244 and Application No. 62/942,276 do not disclose the subject matter of the presently claimed invention. Specifically, the prior applications contemplate an increase of >2 ng/mL sCD28, however, do not contemplate an increase of 1 ng/mL sCD28. The first disclosure of the instant invention as recited is in prior application 63/322,449 filed March 22, 2022. Accordingly, claims 5 and 7 of the instant application are not entitled to the benefit of the PCT/IL2020/051244 date of December 2, 2020 or U.S. Provisional Application No. 62/942,276 filed December 2, 2019.
Should Applicant disagree with the examiner’s factual determination as to the disclosure of the various claim limitations, Applicant may point out the particular places within PCT/IL2020/051244 and 62/942,276 which discloses the specific subject matter.
Accordingly, Provisional Application No. 63/322,449 with the filing date of March 22, 2022 will be used for the purpose of applying art to claims 5 and 7. Claims 1-2, 6, 8-9, and 19-27 are entitled to the benefit of the December 2, 2019 filing date for Provisional Application No. 62/942,276.
Claim Objections
Claims 1-2, 5-6, 19, and 21 are objected to because of the following informalities:
Claims 1-2 and 19 recite the terms time point and/or time points. However, the claims should read timepoint and/or timepoints.
Claim 1 recites steps “a.”, “b.”, “c.”, “d.”, and “e.”, which contain a period after the step letter. MPEP § 608.01(m) states “Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations. See Fressola v. Manbeck, 36 USPQ2nd 1211 (D.D.C. 1995). Replacing the period with a comma will overcome the objection.
Claim 1(e), (line 2) - should read anti-PD-1/PD-L1.
Claim 5 - should read ng/mL.
Claim 6 (line 2) - should read anti-PD-1/PD-L1.
Claim 21 (line 2) - should read “…a checkpoint inhibitor that is not an anti-PD-1/PD-L1 immunotherapy”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The previous rejection of claim 6 under 35 U.S.C. 112(b) as being indefinite has been withdrawn in view of Applicant’s amendment which now clarifies that the recited administration of an increased dose of anti-PD-1/PD-L1 immunotherapy occurs after the second measurement of sCD28 is taken.
The following rejection is necessitated by Applicant’s claim amendments.
Claims 1-2, 6, 8-9, and 19-27 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 1 is 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 and measuring soluble CD28 (sCD28) levels before and after said in said anti-PD-1/PD-L1 immunotherapy. The method further recites that the subject is determined to be a non-responder to said anti-PD-1/PD-L1 immunotherapy if their sCD28 levels increase by a predetermined threshold.
However, it is unclear what the predetermined threshold is and how it is determined? The instant specification provides little clarification, only reciting a broad range of values. For example, the specification discloses that the predetermined threshold value is at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 ng/mL sCD28. Further, in some embodiments the predetermined threshold is an increase of at least 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 75, 80, 90, 95, 100, 125, 150, 175, 200, 250, 300, 350, 400, 450, 500, 600, 700, 750, 800, 900 or 1000% [062]. Therefore, depending on which predetermined threshold is selected, a subject is determined as a non-responder, requiring increased anti-PD-1/PD-L1 administration or alternative therapy. As such, a clinician that selects a threshold value between 10% to 999% increase in sCD28 levels will increase the immunotherapy dosage or administer an alternative immunotherapy according to the instant claims, whereas the same patient would be deemed a responder to treatment if the provider selects a threshold level of 1000% increase in sCD28 levels. This is nonsensical.
Applicant is advised to amend claim 1 to recite the increase in sCD28 levels (ng/mL and/or percentage), or range of levels thereof, that would determine that a subject is a non-responder to anti-PD-1/PD-L1 therapy, such as the levels recited in claim 5 (1 ng/ml sCD28, a 10% increase, or both).
Claims 2, 6, 8-9, and 19-27 are included in the rejection as they depend from or otherwise require all the limitations of the rejected independent claim and fail to clarify the issue.
Claims 1-2, 5-9, and 19-27 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 1 is 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 at two or more time points wherein at least a first time point is before said administering and at least a second time point is after said administering,
determining said subject's sCD28 levels increase from before administering to after administering by at least a predetermined threshold;
diagnosing said subject as a non-responder to said anti-PD-1/PD-L1 immunotherapy, and
further administering an alternative anticancer therapy that is not said anti-PD-1/PD-L1 immunotherapy or administering an increased dose of said anti-PD1/PD-L1 immunotherapy to said subject diagnosed as a non-responder, thereby treating a subject suffering from cancer or at risk of cancer relapse.
The method steps are confusing as written. For instance, it is unclear how one goes from step (c), determining said subject's sCD28 levels increase from before administering to after administering by a predetermined threshold to step (d), diagnosing said subject as a non-responder. The method assumes an increase in sCD28 (i.e., determining said subject’s sCD28 levels increase). However, what if the subject’s sCD28 levels are the same as, or lower than sCD28 prior to anti-PD-1/PD-L1 therapy? The claim provides not alternative.
Additionally, the recitation of the term “increase” in the claims is a relative term. The claim does not specifically indicate what the increase is relative to. Thus, the metes and bounds is unclear.
It is suggested that the method steps be edited to read:
Claim 1. 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 at two or more timepoints wherein at least one timepoint is before administering said anti-PD-1/PD-L1 immunotherapy and at least a second timepoint is after administering said anti-PD-1/PD-L1 immunotherapy,
comparing the sCD28 levels in said subject before administering said anti-PD-1/PD-L1 immunotherapy to the sCD28 levels in said subject after administering said anti-PD-1/PD-L1 immunotherapy;
diagnosing said subject as a non-responder to said anti-PD-1/PD-L1 immunotherapy if the sCD28 levels in said subject increase by at least 10%, 1 ng/ml, or both, and
further administering an alternative anticancer therapy that is not said anti-PD-1/PD-L1 immunotherapy or administering an increased dose of said anti-PD1/PD-L1 immunotherapy to said subject diagnosed as a non-responder, thereby treating a subject suffering from cancer or at risk of cancer relapse.
Claims 2, 5-9, and 19-27 are included in the rejection as they depend from or otherwise require all the limitations of the rejected independent claim and fail to clarify the issue.
Claims 19-20 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 19 recites the method is a method of treating an imminent cancer relapse. However, claim 19 depends from claim 1 which only recites treating a subject at risk of relapse.
Further, the term “imminent” is a relative term. The claim or the specification do not define the term, thus the metes and bounds of the claim are unclear.
Claim 19 also recites the second timepoint is while the subject is responding to immunotherapy. However, the claim depends from claim 1 which implies that there is an increase in sCD28 levels between the first and second timepoints, and such increase indicates the subject is a non-responder to said immunotherapy. Therefore, it is unclear how the patient can be both a responder and a non-responder to anti-PD-1/PD-L1 immunotherapy at the second timepoint which shows an increase in sCD28 levels.
Claim 20 is included in the rejection as it depends from a rejected claim and does not clarify the issue.
Claims 21-24 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 21 recites the alternative cancer therapy of claim 1 is a checkpoint inhibitor that is not an anti-PD-1/PD-L1 immunotherapy. However, claim 1 does not recite that the anti-PD-1/PD-L1 immunotherapy is a checkpoint inhibitor.
Claims 22-24 are included in the rejection because they depend from the rejected claim and do not clarify the issue.
Claims 23-24 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 22 recites the alternative anticancer therapy of claim 21 is a CTLA-4 based immunotherapy.
Claim 23 recites the CTLA-4 based immunotherapy of claim 22 is CTLA-4 checkpoint blockade.
Claim 24 recites the CTLA-4 based immunotherapy of claim 22 is a CTLA-4 inhibitor.
It is not entirely clear from the instant claims or the specification what the difference is between CTLA-4 checkpoint blockade and a CTLA-4 inhibitor.
Specifically, the specification discloses CTLA-4 immunotherapy comprises CTLA-4 blockade. In some embodiments, CTLA-4 immunotherapy comprises administering a CTLA-4 inhibitor. In some embodiments, CTLA-4 immunotherapy comprises administering an anti-CTLA-4 antibody. In some embodiments, the therapy comprises blockade of the CTLA-4 checkpoint [052]. As such, the specification provides no definition or examples to discern the difference between the terms. Therefore, the skilled artisan would not be able to ascertain the metes and bounds of the claims as written.
Claim Rejections - 35 USC § 112(a) - Enablement Withdrawn
The previous rejection of claims 1 and 31 under 35 U.S.C. 112(a) for failing to comply with the enablement requirement has been withdrawn in view of Applicant’s arguments. It should be noted that the rejection set forth in the Office action dated March 5, 2026 erroneously stated that claims 1 and 31 were rejected for lack of enablement. This was a typographical error acknowledged by the Applicant in the responses received May 3, 2026 and June 4, 2026. The rejection should have recited claims 1 and 21-26 were rejected for lack of enablement.
As such, the rejection of claims 1 and 21-26 has been withdrawn in view of Applicant’s arguments.
Specifically, the instant claims are drawn to administering an alternative immunotherapy if the subject is deemed a non-responder to anti-PD-1/PD-L1 therapy based on an increase in sCD28 levels measured before and after administration.
Applicant argues in the reply received June 4, 2026 that the Applicant is enabled for treatment with an alternative immunotherapy.
Applicant’s arguments were fully considered and were deemed persuasive. Specifically, Applicant argues on pages 5-6 that the skilled artisan would recognize that cancer can be treated with alternative therapies (i.e., CTLA-4 inhibitors, CAR-T cell therapy, cancer vaccine), and such therapies may be administered if the primary therapy fails.
The Examiner agrees with Applicant’s arguments and the rejection has been withdrawn.
Claim Rejections - 35 USC § 112(a) - New
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following rejections are set forth after further consideration of the claims.
WRITTEN DESCRIPTION
Claims 1-2, 5-9, and 19-27 are rejected under 35 U.S.C. 112(a), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, at the time the application was filed, had possession of the claimed invention.
As set forth in In re Alonso 88 USPQ2d 1849 (Fed. Cir. 2008), at 1851: The written description requirement of 35 U.S.C. § 112, 1 1, is straightforward: "The specification shall contain a written description of the invention. To satisfy this requirement, the specification must describe the invention in sufficient detail so "that one skilled in the art can clearly conclude that the inventor invented the claimed invention as of the filing date sought." Lockwood V. Am. Airlines, Inc., 107 F.3d 1565, 1572 [41 USPQ2d 1961] (Fed. Cir. 1997); see also LizardTech, Inc. V. Earth Res. Mapping, Inc., 424 F.3d 1336, 1345 [76 USPQ2d 1724] (Fed. Cir. 2005); Eiselstein V. Frank, 52 F.3d 1035, 1039 [34 USPQ2d 1467 (Fed. Cir. 1995).
Alonso at 1852: A genus can be described by disclosing: (1) a representative number of species in that genus; or (2) its "relevant identifying characteristics," such as "complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics." Enzo, 323 F.3d at 964.
Claim 1 is drawn to a method of treating a subject suffering from cancer or at risk of cancer relapse, the method comprising measuring soluble CD28 (sCD28) levels in said subject before and after administration of anti-PD-1/PD-L1 immunotherapy, wherein an increase in sCD28 levels in said subject above a predetermined threshold indicates the subject is non-responsive to said immunotherapy.
Thus the claims encompass any subject of any species and an increase determined by any standard.
First, the specification provides no limiting definition of subject. The specification recites that in some embodiments, the CD28 is mammalian CD28 [047]. Therefore, the subject broadly encompasses any mammal. However, the teachings of the specification are limited to humans subjects. The specification does not provide any teachings to any other mammals.
Burgin (J Mammalogy, 2018; 99(1):1-14; cited IDS 12/15/2025) teaches there are 6,495 species of currently recognized mammals." Benner et al. (Trends Genetics, 2001; 17:414-418; cited IDS 12/15/2025) teaches the assumption of “homology-implies equivalency” which is restricted to a subset of homologs that diverged in the most-recent common ancestor of the species sharing the homologs is not likely. As, two species living in the same space, almost by axiom, cannot have identical strategies for survival. This, in turn, implies that two orthologous proteins might not contribute to fitness in exactly the same way in two species [pg. 414]. For example, Benner teaches that although the leptin gene homologs have been found in mice and humans, their affect is different. Specifically, the leptin gene in mice plays a major role in obesity, but no such effect has been demonstrated in humans due perhaps to the different evolutionary forces [pg. 414-415]. Benner thus teaches that the activity and function of genes in different species is unpredictable.
Second, the specification provides no specific guidance on how to measures sCD28. The specification discloses the detection is by a secondary antibody. In some embodiments, the detection is with a tagged molecule that binds the sCD28. In some embodiments, the detection is by ELISA. In some embodiments, the detection is by immunohistochemistry. In some embodiments, the detection is by immunoblot [067].
The state of the art teaches multiple methods for detecting sCD28 levels in humans. For example, Malkawi et al. (Clinica Chimica Acta, 2023; 548:117501) teaches sCD28 measured via LC-MS/MS can be used as a biomarker for rheumatoid arthritis [Title]. Additionally, Aprillia et al. (Immun Ageing, 2024; 21:9) teaches sCD28 is a biomarker that can be used to detect immunosenescence using flow cytometry [Title, Background]. Furthermore, Sun et al. (Central Eur J Immunol, 2014; 39(2):216-222; cited 3/22/2023) teaches soluble CD28 can be measured using ELISA as a biomarker for Graves’ disease diagnosis [Title, Abstract].
Thus, the specification has not provided no specific guidance on how to perform the perform the method in vivo with any mammalian subject. Thus, the specification does not provide adequate written description for the breadth of the claims as submitted.
Claims 2, 5-9, and 19-27 are included in the rejection as they depend from or otherwise require all the limitations of a rejected claim.
ENABLEMENT
Claims 1-2, 5-9, and 19-20 are rejected under 35 U.S.C. 112(a), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Claim 1 is rejected under 35 U.S.C. 112(a), first paragraph, because the specification, while being enabling for administering an alternative anticancer therapy that is not said anti-PD- 1/PD-L1 immunotherapy if the subject is deemed a non-responder to said immunotherapy; does not reasonably provide enablement for administering an increased dose of said anti-PD1/PD- L1 immunotherapy if the subject does not respond to said anti-PD1/PD- L1 immunotherapy.
The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
As a general rule, enablement must be commensurate with the scope of claim language. MPEP § 2164.08 states, “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation.” In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)” (emphasis added). The “make and use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” The principle was explicitly affirmed in Auto. Tech. Int’l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008). See also In re Cortright, 49 USPQ2d 1464, 1466 and Bristol-Myers Squibb Co. v. Rhone-Poulenc Rorer Inc., 49 USPQ2d 1370.
The factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). Among these factors are: (1) the nature or the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary. When the above factors are weighed, it is the examiner’s position that one skilled in the art could not practice the invention without undue experimentation. Some experimentation is not fatal; the issue is whether the amount of experimentation is “undue”; see In re Vaeck, 20 USPQ2d 1438, 1444.
(1) The nature of the invention and (5) The breadth of the claims:
Claims 1 is drawn to a method of treating a subject suffering from cancer or at risk of cancer relapse, the method comprising measuring sCD28 levels before and after administering an anti-PD-1/PD-L1 immunotherapy, and administering an alternative therapy or an increased dose of said anti-PD-1/PD-L1 immunotherapy if the patient is deemed a non-responder to said immunotherapy as determined by an increase in sCD28.
Claim 6 limits the treatment options to administering an increased dose of said anti-PD-1/PD-L1 immunotherapy if the subject is a non-responder to said immunotherapy.
Nowicki et al. (Cancer J, 2018; 24(1):47–53) teaches cancer immunotherapy utilizing blockade of the PD-1/PD-L1 checkpoint has revolutionized the treatment of a wide variety of malignancies, leading to durable therapeutic responses not typically seen with traditional cytotoxic anti-cancer agents. However, these therapies are ineffective in a significant percentage of patients, and some initial responders eventually develop resistance to these therapies with relapsed disease. The mechanisms leading to both primary and acquired resistance to PD-1/PD-L1 inhibition are varied, and can be both multifactorial and overlapping in an individual patient [Abstract].
Nowicki further teaches that patients treated with PD-1/PD-L1 blockade who never demonstrate a clinical response or stabilized disease are referred to as having primary resistance to therapy [pg. 3, par. 1]. There are a subset of patients who exhibit long-lasting responses to treatment. However, some patients acquire resistance over time, either eventually progressing while on therapy despite an initially robust response, or who are unresponsive to re-initiation of checkpoint blockade [pg. 7, par. 2].
(2) The state of the prior art and (4) The predictability or unpredictability of the art:
Regarding the current state of the art in anti-PD-1/PD-L1 immunotherapy, Renner et al. (Matter, 2022; 5(3):975-987) teaches maximum tolerated dose (MTD), a dose selection strategy that derives from cytotoxic agent development, has proven challenging for checkpoint inhibitors and molecularly targeted agents because there is no clear dose-response relationship, and the identification of an MTD may not be a realistic objective. In fact, in studies performed with pembrolizumab, ipilimumab, atezolizumab, durvalumab, and nivolumab, investigators did not identify an MTD.
Renner further teaches anti-PD-1 inhibitors pembrolizumab and nivolumab have shown similar response rates in a wide range of doses because the programmed death-1 receptor reaches maximum occupancy at low doses for these agents, translating into a flat exposure-response curve, where increasing the dosage does not lead to an increase in tumor response [Context Box].
Given the predictability that administrating an increased dose of an anti-PD-1/PD-L1 monotherapy does not increase the therapeutic benefit, one of ordinary skill in the art would not increase the dose of an anti-PD-1/PD-L1 monotherapy if the patient had primary or acquired resistance to said monotherapy.
6) the amount of direction or guidance provided by the inventor; 7) the existence of working examples;
The instant specification sets forth examples demonstrating the relationship of sCD28 levels and cancer progression during immunotherapy. Example 1 measured sCD28 in over 100 serum samples taken from melanoma patients before and throughout treatment with nivolumab. It was found that subjects with low levels (< 2 ng/mL) had longer median survival than those with high levels [0214]. Example 2 measured sCD28 in 166 serum samples taken from melanoma, renal cell carcinoma, lung squamous cell carcinoma, and urothelial carcinoma patients undergoing anti-PD-1 immunotherapy (nivolumab or pembrolizumab), anti-PD-L1 immunotherapy (atezolizumab), and anti-CTLA-4 immunotherapy (ipilimumab). Out of those, 37 individuals were positive for sCD28 (> 2 ng/mL). However, results were always consistent, with responders demonstrating a decrease in sCD28 and non-responders demonstrating an increase in sCD28 [0215]. Example 3 demonstrates the relationship of sCD28 during relapse. Two patients from Example 2 demonstrated alternating kinetics during immunotherapy. Both patients responded to immunotherapy, with the first (urothelial carcinoma) showing complete response (CR) and the other (melanoma) showing partial response (PR). During remission both patients were negative for sCD28. However, both patients showed a marked increase in sCD28 just before or at initiation of cancer relapse. The sCD28 levels increased in the CR patient from week 46 and on as the patient entered a stage of progressive disease. The PR patient had an increase in sCD28 levels from week 35 on as they entered a phase of stable disease [0218]. The specification further discloses that 60 additional plasma samples from patients with melanoma, lung cancer, renal cancer, H&N cancer, bladder cancer, mesothelioma and kidney cancer undergoing anti-PD 1 immunotherapy (nivolumab or pembrolizumab) were examined for their sCD28 levels before and during therapy. The patients' response to therapy was monitored for 12 months after initiation of the therapy and each subject was categorized as either a responder or non-responder to the immunotherapy. Six patients initially responded to the immunotherapy, but eventually relapsed within the first year from therapy initiation. Of these 6 relapse patients, 5 already showed increased levels of sCD28 after 6 months of therapy. Most of these 5 were still considered "responders" at this point as it was before relapse had been clinically identified [0218].
However, there are no examples wherein a non-responder was administered an increased dose of the anti-PD-1 monotherapy. Therefore, the only embodiment that is enabled is administering an alternative therapy that is not the same anti-PD-1/PD-L1 immunotherapy to a subject that has an increase in sCD28 levels as such they are deemed a non-responder to said anti-PD-1 immunotherapy. One of skill in the art would be required to engage in extensive, difficult experimentation to identify an both the patient population and the specific anti-PD-1/PD-L1 inhibitor that is able to overcome acquired resistance to the initial immunotherapy, which is known to be challenging as indicated above. This required experimentation is undue.
In conclusion, the claimed invention does not provide enablement for further administering an increased dose of said PD-1/PD-L1 immunotherapy to said subject. Thus for the reasons outlined above, the specification is not considered to be enabling for one skilled in the art to make and use the claimed invention as the amount of experimentation required is undue, due to the broad scope of the claims, the lack of guidance and working examples provided in the specification. Therefore, the specification is not representative of the instant claims and the specification is not fully enabled for the instant claims. In view of the above, one of skill in the art would be forced into undue experimentation to practice the claimed invention.
Claims 2, 5-9, and 19-20 are included in the rejection as they depend from or otherwise require all the limitations of a rejected claim.
Claim Rejections - 35 USC § 103 - Withdrawn
The previous rejection of claims 1-9 and 19-26 under 35 U.S.C. 103 has been withdrawn in view of Applicant’s arguments. Specifically, the claims were rejected as being unpatentable of Hakim et al. (WO 2019/175885; cited IDS 3/22/2023). However, Applicant has argued on page 7 of the reply received June 4, 2026 that Hakim does not qualify as a prior art reference as it was published September 19, 2029, which is less than 1 year prior to the earliest benefit date of December 2, 2019. Further, although the instant invention and Hakim do not share all the same inventors, the inventions of Hakim and the instant application are commonly assigned to Biond Biologics Ltd.
Applicant’s arguments were fully considered and the rejection has been withdrawn because the prior art reference has been disqualified.
Closest Prior Art
There is no prior art that teaches or suggests a method for treating a subject suffering from cancer or at risk of cancer relapse comprising measuring sCD28 levels before and after anti-PD-1/PD-L1 immunotherapy and administrating an alternative therapy if the sCD28 levels increase above a threshold level, therefore indicating the subject is a non-responder to said anti-PD-1/PD-L1 immunotherapy.
The closest prior art, Wang et al. (J Immunotherapy Cancer, 2019; 7(334):1-9), teaches soluble CD28 levels are associated with poor outcome in clear cell renal cell carcinoma patients, although not significantly, with sCD28 negatively correlated with the number and cytolytic activity of T cells. However, Wang does not teach or suggest any association between sCD28 levels during the course of anti-PD-1/PD-L1 immunotherapy using sCD28 levels for diagnosing a patient as a non-responder to said immunotherapy.
Double Patenting - Withdrawn
In view of Applicant’s arguments presented on page 7 of the reply received June 4, 2026, the nonstatutory double patenting rejection of claims 1-9 and 19-26 over the claims of U.S. Patent No. 12,139,534 has been withdrawn.
Specifically, Applicant argues that the issued patent is drawn to improving anti-PD/PD-L1 based immunotherapy by reducing sCD28 levels. However, the instant claims are drawn to administering an alternative therapy if the subject is a non-responder to said anti-PD/PD-L1 based immunotherapy and do not overlap in scope.
Applicant’s arguments were fully considered are deemed persuasive.
Accordingly, the previous nonstatutory double patenting rejection has been withdrawn.
Double Patenting - Maintained/Updated
Pursuant to 37 CFR 1.78(f), when two or more applications filed by the same applicant or assignee contain patentably indistinct claims, elimination of such claims from all but one application may be required in the absence of good and sufficient reason for their retention during pendency in more than one application. Applicant is required to either cancel the patentably indistinct claims from all but one application or maintain a clear line of demarcation between the applications. See MPEP § 822.
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4, 6-7, 9-10, 12, 16, 20, 27-28, 31, and 36 of copending Application No. 17/781,966 in view of Zhao et al. (Frontiers Pharmacol, 2019; 10:1184), Cherkassky (J Clin Invest, 2016; 126(8):1-16), and Rotte (J Exp & Clin Can Res, 2019; 38:255).
Although the claims at issue are not identical, they are not patentably distinct from each other because they are coextensive in scope. Copending claim 1 is drawn to a method of determining response to PD-1/PD-L1 based immunotherapy in a subject suffering from cancer, the method comprising measuring sCD28 levels in said subject at least two time points wherein at least one of those time points is after initiation of said PD-1/PD-L1 based immunotherapy, wherein an increase in sCD28 levels from a first time point to a second time point after initiation of said PD-1/PD-L1 based immunotherapy indicates said subject is not a responder to said immunotherapy and a decrease or no change in sCD28 levels from said first time point to said second time point after initiation of said PD-1/PD-L1 based immunotherapy indicates said subject is a responder to said immunotherapy, optionally wherein a decrease is a decrease of at least 1 ng/ml sCD28, thereby determining response to PD-1/PD-L1 based immunotherapy in a subject. Copending claims 2, 4, and 6 are drawn to the dosing schedule for the anti-PD-1/PD-L1 immunotherapy, wherein the first timepoint is before initiation of said immunotherapy and the second point is 7 weeks after. Copending claim 7 recites a decrease in sCD28 levels from the first and second timepoint indicates the subject is a responder to said immunotherapy. Copending claim 9 recites that said immunotherapy is discontinued and a different immunotherapy is administered if the subject is a non-responder, or if the subject is a responder, the immunotherapy is continued or an increased dose of immunotherapy is administered. Copending claim 10 is drawn to a method of diagnosing or predicting cancer relapse in a subject in need thereof, the method comprising receiving a sample obtained from said subject; measuring soluble CD28 (sCD28) levels wherein an increase in sCD28 levels indicates cancer relapse within the next 20 weeks from said measuring, or diagnosing said subject with said increase as having cancer relapse within the next 20 weeks, administering an immunotherapy to a subject diagnosed with or predicted for cancer relapse. Copending claim 12 recites the subject has undergone PD-1 or PD-L1 immunotherapy. Copending claim 16 recites said increase is at least 1 ng/mL sCD28. Copending claim 20 recites the sample is a blood sample. Copending claims 27-28 recite the types of cancer to be treated, including melanoma and urothelial cancers. Copending claim 31 recites that the immunotherapy is selected from a checkpoint inhibitor, optionally wherein said checkpoint inhibitor is a PD-1 and/or PD-L1 based immunotherapy.
The methods of the copending claims read on the instant invention. The copending claims differ from the instant claims in that copending claim 10 recites immunotherapy comprises anti-PD-1/PD-L1 immunotherapy, CAR based therapy, cancer vaccine, or anti-CTLA-4 immunotherapy, however, the copending claims do not recite these are alternative therapies as recited in the instant claims.
However, 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 an alternative immunotherapy would be administered if the subject is indicated to be at risk of cancer relapse based on an increase in sCD28, such as a cancer vaccine, CAR based therapy, or anti-CTLA-4 immunotherapy after first-line treatment fails. For example, Zhao et al. (Frontiers Pharmacol, 2019; 10:1184) teaches malignant tumors evade immune surveillance by utilizing inhibitory immunoregulatory mechanisms, especially immune checkpoint receptor pathways. Immune checkpoint inhibitors (ICIs) can enhance antitumor immune response by blocking negative regulation signaling, however, ICI monotherapy does not always achieve clinical improvement in some cancers. Zhao et al. further teaches that ICIs can be combined with therapeutic cancer vaccines to enhance their clinical effects in a synergistic manner [pg. 2, col. 1, par. 1-2]. Zhao et al. teaches pembrolizumab in combination with the T-VEC vaccine for the treatment of unresectable stages IIIB to IV melanoma resulted in an ORR of 62%, which was twice as was observed with pembrolizumab alone [pg. 5, col. 1, par. 2]. Additionally, Cherkassky (J Clin Invest, 2016; 126(8):1-16) teaches success of antibody-mediated checkpoint blockade requires a relatively high mutation burden and the presence of infiltrating T cells. Adoptive transfer of tumor-targeted T cells may fill the void, and strategies that combine adoptive T cell therapy with checkpoint antibody blockade have shown that antibody-mediated checkpoint blockade effectively provides reversal of immuno-inhibition in a systemic fashion [pg. 3130, col. 2]. The combinatorial strategy of costimulation and checkpoint blockade enhanced T cell function resulting in long-term tumor-free survival following infusion of a single low dose of CAR T cells [pg. 3140, Discussion, par. 1]. Lastly, Rotte (J Exp & Clin Can Res, 2019; 38:255) teaches drugs targeting PD-1 or its ligand PD-L1 have been approved for treatment of different types of cancers. Initial studies show that when these drugs are administered as monotherapy, they demonstrate a dramatic increase in durable response rates and have manageable safety profiles, but more than 50% of patients fail to respond to treatment. Subsequently, combination of CTLA-4 and PD-1 blockers were evaluated to increase the response rates in patients. Rotte teaches ipilimumab (anti-CTLA-4) plus nivolumab (anti-PD-1) was shown to significantly enhance efficacy in metastatic melanoma patients, and the combination therapy has since been approved for treatment of metastatic melanoma, advanced renal cell carcinoma and metastatic colorectal cancer, with efficacy of the combination shown in other cancer types [Abstract].
Therefore, the skilled artisan would have a reasonable expectation of success in administering an immunotherapy as recited in the copending claims as an alternative therapy if/when the subject has an increase in sCD28 levels before and after initiation of a primary therapy. As such, the instant claimed invention is an obvious modification of the claims of the copending application in view of the prior art references and the rejection is maintained.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claim is allowed.
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.
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/MAUREEN VARINA DRISCOLL/ Examiner, Art Unit 1642 /SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
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