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 .
Applicant filed a response to the Non-Final Action of 3/31/206 on 6/29/2026. Claims 1-15, 17 are canceled. Claims 16, 18-27 are under examination.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 6/29/2026 was considered by the examiner.
Withdrawn Rejections
112d: Regarding the rejection of claim 17 for failing to further limit, applicant canceled claim 17. The rejection of claim 17 is withdrawn.
103: Regarding the rejection of claims 16-27 as being rejected under 103 as being unpatentable over US 4613322 (Edelson), Jackson et al. Support Care Cancer 23, 1-3 (2015) and Ni et al., Front. Immunol. 10: 457, the rejection is withdrawn. A new rejection to address these claims is below.
New Rejections
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.
Claims 16-27 are rejected under 35 U.S.C. 103 as being unpatentable over
Fujita et al., 2019, “Ubiquitin Ligases in Cancer Immunotherapy—Balancing Antitumor and Autoimmunity“, Trends in Molecular Medicine, 25: 428-443 in view of
Budde et al., 2017, “In vitro effects of different 8-methoxypsoralen treatment protocols for extracorporeal photopheresis on mononuclear cells”, Cent. Eur. J. Immunol, 42: 1-9 and
Lomax et al., 2018, “Immune Toxicity with Checkpoint Inhibition for Metastatic Melanoma: Case Series and Clinical Management”, Journal of Skin Cancer, 2018: 13 pages.
Couey et al., 2019, “Delayed immune-related events (DIRE) after discontinuation of immunotherapy: diagnostic hazard of autoimmunity at a distance”, Journal for ImmunoTherapy of Cancer, 7: 11 pages.
Fujita et al., teach that despite the remarkable success of immune checkpoint blockers (ICBs), autoimmune adverse events have been reported in clinical trials of anti-CTLA-4 and anti-PD-L1/PD-1 antibodies as anticancer therapies. Severity varies with the ICB, but the most commonly affected organs are skin, gastrointestinal tract, liver, and endocrine organs, with thyroid events being more common in patients treated with anti-PD-1. Fujita et al. teach that it remains unknown how ICBs elicit irAEs, but elucidating these mechanisms is crucial to prevent life-threatening events and to guide the development of ICBs. Aberrant T and B cell activation seen following ICB treatment can elicit irAEs because both antitumor and self-reactive cells are reinvigorated. Accordingly, nonspecific expansion of T cell clonotypes following anti-CTLA-4 or combined CTLA-4/PD-1 therapy, and altered effector function of circulating T cells following PD-1 blockade, and correlated with irAE. T cells recognizing tumor cells may also cross-react with self-antigens following ICB or other immunotherapies. Similarly, alterations in B cells following combination ICB may predict irAE risk in melanoma patients, and baseline antibody levels (suggestive of a pre-existing autoimmune condition) may predict irAEs in melanoma or non-small cell lung cancer patients (Fujita et al., Box 1).
Budde et al. teach that the main advantage of extracorporeal photopheresis (ECP) is the induction of selective immune tolerance instead of unspecific immunosuppression. The therapeutic effect of ECP is mediated by effects initiated by the reinfusion of apoptotic cells rather than by simple reduction of GvHD causing cytotoxic T-cells. Following apoptotic cell infusion, dendritic cell differentiation via platelet activation and induction of regulatory T cells are important pathways leading to subsequent immune tolerance (Budde et al., introduction). Budde et al. teach that the general mechanism of selective immunologic silencing has a considerable potential for treatment of diseases with a hyper-reactive immune system (Budde et al, page 7, 1st parag. under Discussion). Budde et al. teach that Tregs are most probably the central effector cells in ECP-mediated induction of immune tolerance, the effect probably contributes to the therapeutic mechanisms of ECP treatment by shifting the T cell ratio from T-helper and cytotoxic T cells to the Treg fraction (Budde et al., page 8, 1st col., 2nd parag.).
At the time the invention was made, one would have used ECP on patients who receive ICI therapy and experience irAE. One would have done so because Fujita et al. teach that irAE is an autoimmune adverse event characterized by aberrant T and B cell activation where antitumor and self-reactive cells are reinvigorated and Budde et al. teach that ECP has considerable potential for treatment of diseases with a hyper-reactive immune system. Further, Budde et al. characterize the therapeutic effect of ECP results from immune tolerance rather than immunosuppression. There would have been reasonable expectation of success because Budde et al. indicate that ECP is a treatment that leads to immune tolerance.
While Fujita et al. and Budde et al. teach ICI, cancer and irAE generally, they do not specifically teach autoimmune hepatitis (e.g. claim 16) or melanoma (e.g. claim 21).
Lomax et al. teach that immune checkpoint inhibitors (ICI) (anti-PD1 and anti-CTLA-4) are a standard of care for advanced melanoma. Novel toxicities comprise immune-related adverse events (irAE). With increasing use, irAE require recognition, practical management strategies, and multidisciplinary care (Lomax et al., abstract). Lomax et al. teach that in clinical trials, the rate of significant hepatitis or deranged liver function is identified at <1-2% for anti-CTLA-4 agents, 1-2% with anti-PD-1 therapies and 6-8% with combined therapy. Grade 3-4 hepatotoxicity in their cohort was 5%. 2 patients in their cohort developed hepatic toxicity required treatment with mycophenolic acid or mycophenolate mofetil. Methylprednisolone required to treat transplant rejection has been used for ipilimumab-induced hepatotoxicity. Methylprednisolone is suggested for steroid-refractory hepatitis and is consider part of disease management (Lomax et al., 2nd parag. under 4.4 Management of Refractory Hepatitis and Gastrointestinal Toxicity). Table 3 also indicates that patients are monitored for 4 grades of hepatic irAE. At Grade 2, checkpoint inhibitor therapy is delayed until improving to baseline. At Grades 3/4, checkpoint inhibitor therapy is discontinued.
At the time the invention was made, one would have administered Budde et al.’s ECP to Lomax et al.’s melanoma patients who exhibit autoimmune hepatitis. One would have done so in order to reduce autoimmune hepatitis. There would have been reasonable expectation of success as irAE results from a hyper-active immune system and ECP is a treatment that can be used to modulate the immune cells into tolerance.
Regarding claims 16, 19, 20 where a photosensitizing agent is added to a blood sample from a subject and subjecting the sample to irradiation, Budde et al. teach blood cells obtained from the patient, 8-methoxypsoralen (8-MOP), and UVA (Budde et al., page 2 under Materials and Methods). It is noted that while Budde et al. teach blood obtained from healthy patients, one would understand that in a clinical setting, the blood is obtained from an irAE patient (see for example, Budde et al. who teach that ECP therapy begins with an apheresis step in which about 10% of the patient’s peripheral leukocytes are harvested, Budde et al., page 1, 2nd col., 1st parag.).
Regarding claim 18, wherein the method results in generation or induction of NK cells in the sample, while Budde et al. do not specifically indicate that NK cells were induced or generated, the generation or induction of NK cells would have been an outcome resulting from ECP as the steps taught by Budde et al. are the same as that recited in the claims.
Regarding claim 21 being drawn to malignant melanoma, Lomax et al. teach malignant melanoma (see title).
Regarding claim 22 being drawn to checkpoint inhibitor therapy being discontinued after symptoms of irAE occurred in the patient, Table 3 of Lomax et al. teach that ICI is discontinued in malignant melanoma patients who have liver irAE.
Regarding claim 23 being drawn to symptoms of irAE that occurred after the checkpoint-inhibitor therapy was discontinued, Couey et al. teach that there are patients who show delayed immune-related events (DIRE) after discontinuation of immunotherapy. Couey et al. identifies DIRE as an autoimmune condition (Couey et al., title and abstract (Background)). Couey et al. indicates the importance of identifying DIRE as irAE is generally manageable with prompt initiation of treatment (Couey et al., abstract (Conclusion)). Couey et al. identified DIRE patients, including one who exhibited irAE in the liver (Couey et al., Figure 2).
It would have been obvious for an artisan to identify DIRE patients who exhibit irAE in the liver after immunotherapy had been discontinued. One would have done so as Couey et al. teach that identification of DIRE patients would reduce morbidity resulting from diagnostic delay. Further, one would have applied ECP to these patients as Budde et al. teach that ECP is an effective treatment for autoimmune disease.
Regarding claim 24 being drawn to symptoms of irAE were maintained after the checkpoint inhibitor therapy was discontinued, Table 3 of Lomax et al. shows that Grade 3/4 irAE liver patients continue to have symptoms of irAE as they are treated with steroids or immunosuppressants.
Regarding claim 25 being drawn to the ICI being anti-CTLA-4 and anti-PD1, Lomax et al. teach treatment of patients with anti-PD-1 antibody, wherein some patients had received anti-CTLA-4 antibody prior to treatment with anti-PD-1 (Lomax et al., abstract).
Regarding claims 26 and 27 being drawn to the patient concurrently receiving an immune suppressive drug and/or is refractory to immunosuppressive drug, Lomax et al. teach that the two irAE Grade 3/4 liver patients were treated with methylprednisolone and mycophenolate mofetil (Lomax et al., page 5, under 4.3. Gastrointestinal and Hepatic Toxicity).
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 16-27 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 12491248 (‘248) in view of
Lomax et al., 2018, “Immune Toxicity with Checkpoint Inhibition for Metastatic Melanoma: Case Series and Clinical Management”, Journal of Skin Cancer, 2018: 13 pages.
Instant claims 16-27 overlaps with claims 1-20 of ‘248 regarding treating a blood sample from a cancer patient treated with checkpoint inhibitors and will develop or has developed symptoms of irAE with 8-methoxypsoralen and UVA and returning the treated blood to the patient. The instant claims differ from ‘248 claims in that the instant claims, the irAE is hepatitis, and ‘248, the irAE is colitis.
Lomax et al. teach irAE colitis in cancer patients treated with anti-CTLA4 and anti-PD-1 (Lomax et al., page 5, 2nd col., under 4.4. Management of Refractory Hepatitis and Gastrointestinal Toxicity).
It would have been obvious for an artisan to substitute irAE colitis patients with irAE hepatitis patients as both populations are the result of irAE that develops following anti-CLTA4 and anti-PD-1 treatment. There would have been reasonable expectation of success since the underlying cause of irAE (autoimmunity) is the same between both irAE colitis and hepatitis patients.
Conclusion
No claims allowed.
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/JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647
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