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
Preliminary amendment filed on 08/08/2023 is acknowledged. Claims 4-7 and 18-20 were amended and claims 2-3, 8-12, 15-17, and 21-28 were canceled. Claims 1, 4-7, 13-14, and 18-20 are pending in the instant application and are examined on the merits herein.
Priority
This application is a National Stage Application of PCT/US2022/015670, filed on 02/08/2022 and claims benefit of 63/147,234 filed on 02/08/2021.
Information Disclosure Statement
The information disclosure statements (IDS) dated 08/08/2023, 02/19/2024, and 11/20/2024 comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609, except where noted. Accordingly, the IDS documents have been placed in the application file and the information therein has been considered as to the merits.
Claim Rejections - 35 USC § 112(a)
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.
Claims 1, 4-7, 14,and 18-20 are rejected under 35 U.S.C. 112(a), because the specification, while being enabling for inhibiting, decreasing or reducing donor organ or tissue rejection by administering to the recipient subject or to the donor organ or tissue ex vivo an effective amount of a small molecule CD38, it does not reasonably provide enablement for treating (as defined to include preventing on instant specification page 9), prophylaxis (as defined to be interchangeable with preventing on instant specification page 10), or preventing donor organ or tissue rejection. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
With respect to the claimed method, attention is directed to In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. (1) the nature of 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.
All of the Wands factors have been considered and those most relevant to the cited claims are discussed below.
Nature of the invention: The invention is drawn a method for preventing donor organ or tissue rejection by administering an effective amount of a small molecule CD38 inhibitor to a recipient subject or to the donor organ or tissue ex vivo.
Relative skill of those in the art: The relevant art is pharmaceutical formulations, which is a mature art where practitioners receive specialized training and earn advanced degrees during the course of their study. There is a voluminous amount of published material describing research, best practices and practical application of compositions and techniques to the medical field. The relative skill of those in the art is high.
Breadth of claims: The claims are broad with respect to the concept of prevention. The full scope of the instant claims covers the entire definition of treatment and prevention as well any adverse effect from an organ or tissue transplant. The specification defines “prevention” as meant to stop a particular event or characteristic, to stabilize or delay the development or progression of a particular event or characteristic, or to minimize the changes that a particular event or characteristic will occur (specification page 9). The full scope of the claims encompasses the entire definition of tertiary prevention, which covers reducing the occurrence of or eliminating a symptom or condition. The term “prevention” is assumed to take on the customary meaning known to those skilled in the art. Specifically, “prevention” is defined according to the Institute for International Medical Education (Wojtczak, 2002) as: the goals within the field of medicine to promote health, to preserve health, to restore health when it is impaired, and to minimize suffering and distress. Customarily prevention is sub-classified as primary (the protection of health by personal and community wide effects), secondary (the measures available to individuals and populations for the early detection and prompt and effective intervention to correct departures from good health) and tertiary (the measures available to reduce or eliminate long-term impairments and disabilities, minimize suffering caused by existing departures from good health, and to promote the patient's adjustment to irremediable conditions). Tertiary prevention is most relevant as used in the context of the instant invention. Thus, the intent of the method, as interpreted by a skilled practitioner of the medical or pharmaceutical arts, would include that which reduces the occurrence of, or eliminates, a donor organ or tissue rejection.
Amount of guidance/Existence of working examples: The instant specification provides experimental results on the CD38 inhibition and macrophage and animal transplant (instant specification example 4, page 65). The results showed that administration of a CD38 inhibitor to mouse Kupffer cells exposed to hypoxia-reoxygenation resulted in cell viability compared to an untreated control (instant specification Figure 8). Further, the instant specification shows the results of skin allograft and heart allograft mice treated with a CD38 inhibitor that maintained viable skin and cardiac allografts compared to vehicle treated controls (instant specification Figure 10).
State of the prior art/Predictability or unpredictability of the art: Nickerson (The American Society of Transplantation and the American Society of Transplant Surgeons, published 03/09/2020, pages 12-22) is drawn to the study of antibody-mediated rejection in kidney transplantation (title). Nickerson teaches that whereas current short-term kidney transplant and patient survival is outstanding (>95% 1-year) and acute rejection rates are low (5%- 15%), long-term kidney transplant survival remains suboptimal with a half-life of 11-15 years. Although the etiology of late allograft failure is multifaceted, immune-mediated injury (evidence of insufficient immunosuppression) and off-target morbidities of immunosuppressive medications are major contributors. In recent years, novel solid-phase single-antigen bead (SAB) assays to detect HLA donor-specific antibodies (DSAs), coupled with protocol biopsy studies, have led to the recognition that antibody-mediated rejection (ABMR) is frequently involved in early and late kidney allograft loss. ABMR remains one of the major challenges facing transplant medicine. There are no FDA-approved treatments for acute or chronic ABMR (page 12).
Quantity of experimentation: One of ordinary skill in the art would have to conduct a myriad number of experiments comprising trial and error administration of the claimed compositions to donor organ or tissue recipients or to donor organs or tissue ex vivo to determine if the claimed compositions can be used in the fully claimed scope to treat and prevent donor organ or tissue rejection. Further, even with tests, it would be difficult to determine which patients would or would not experience long-term organ transplant rejection. Genetech, 108 F.3d at 1366, states that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion” and “[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable”.
Therefore, in view of the Wands factors as discussed above, e.g., the breadth of the claims, the amount of guidance provided, the state/unpredictability of the art and the lack of working examples, one of skill in the art would be burdened with undue experimentation to practice the invention commensurate in the scope of the claims, with no assurance of success. Claims 4-7 and 18-20 are rejected for being dependent on a rejected claims base.
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.
Claims 1, 5-7 and 20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Shoskes et al. (Transplantation, published 12/15/2005, see IDS dated 08/08/2023) as evidenced by Escande et al. (Diabetes, published 03/13/2014, see IDS dated 08/08/2023) and as evidenced by Pubchem (https://pubchem.ncbi.nlm.nih.gov/compound/quercetin, published 10/05/2020, accessed 12/02/2025, see PTO-892).
Shoskes is drawn to the study of the beneficial effects of the bioflavonoids curcumin and quercetin on early function in cadaveric renal transplantation (title). As evidenced by Escande, quercitin is a CD38 inhibitor (abstract). Shoskes exemplifies the administration of a combination of curcumin and quercetin to 45 cadaveric kidney transplant recipients (page 1556, right column). Acute rejection incidence was the lowest in the high dose of the combination of curcumin and quercetin (abstract).
Regarding instant claims 6 and 7, the treatment was started within 24 hours of surgery and continued for 1 month (page 1556, right column).
Regarding instant claim 20, as evidenced by Pubchem, quercetin has a molecular weight of 302.23 g/mol.
Accordingly, the instant claims are anticipated by the prior art.
Claim 13 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Escande et al. (Diabetes, published 03/13/2014, see IDS dated 08/08/2023).
Escande is drawn to the study of apigenin as an inhibitor of NAD+ase CD38. Escande exemplifies the administration of apigenin and quercetin in vitro and shows that apigenin and quercetin inhibit CD38 activity and increases NAD+ levels in A549 cells (page 1088, left column).
Accordingly, the instant claim is anticipated by the prior art.
Claims 14, 18 and 19 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Gochi et al. (Transplantation Direct, published 11/10/2020, see PTO-892) and as evidenced by Escande et al. (Diabetes, published 03/13/2014, see IDS dated 08/08/2023).
Gochi is drawn to a preservation solution containing quercetin and sucrose for porcine kidney transplantation (title). Gochi teaches that in organ transplantation, the University of Wisconsin (UW) solution has been the gold standard for organ preservation. Quercetin has numerous antioxidant and anti-inflammatory activities, and sucrose may be effective for cold storage (CS). Gochi teaches that the addition of quercetin and sucrose to a UW solution can improve kidney preservation and potentially enhance the outcome of kidney transplantation (abstract). Although Gochi does not expressly teach the method for tissue rejection, as they state that the method can enhance the outcome of kidney transplantation, one would have immediately envisioned this as a method to treat organ or tissue rejection (see MPEP 2131.02 (III)). Gochi teaches that further studies should be performed to investigate the potential application of quercetin and sucrose in kidney transplantation and kidney preservation (page 9, column 1). As evidenced by Escande, quercetin is a CD38 inhibitor (abstract). Gochi teaches that preservation with quercetin and sucrose showed a tendency for lower oxidated stress, better renal function, and lower I/R injury and that these results indicate the possibility of clinical application of quercetin in organ preservation (page 8, column 2). Gochi exemplifies the treatment of porcine kidney grafts preserved with CS for 22 hours and perfused with HOPE with the CS/MP-UW solution with quercetin and sucrose. The kidney grafts were then transplanted (page 3).
Accordingly, the instant claims are anticipated by the prior art.
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 1 and 4 are rejected under 35 U.S.C. 103 as being unpatentable over Jordan et al. (WO 2020/185672 A1, published 09/17/2020, see PTO-892) and Shoskes et al. (Transplantation, published 12/15/2005, see IDS dated 08/08/2023) and as evidenced by Escande et al. (Diabetes, published 03/13/2014, see IDS dated 08/08/2023).
Jordan is drawn to the use of anti-CD38 agents for desensitization and treatment of antibody-mediated rejection of organ transplants (title). Jordan teaches methods for desensitizing a human leukocyte antigen (HLA) sensitized subject to prepare for an organ transplant with an improved transplant survival and function, and/or treating or reducing the likelihood of antibody mediated rejection (ABMR) of an organ transplant in a subject, generally including administering an effective amount of an anti-CD38 antibody or a CD38-targeting therapy to reduce the symptoms or ABMR or HLA levels. The subject in the methods may have developed or is experiencing drug-resistant sensitization, and to whom standard techniques like intravenous immunoglobulin and plasmapheresis are ineffective (abstract). The subject can be one who is further resistant or has acquired resistance to immunosuppressive treatment with one or more of eculizumab, thymoglobulin, bortezomib, carfilzomib, basiliximab, mycophenolate mofetil, tacrolimus and corticosteroids (paragraph 0019).
Jordan does not teach a CD38-targeting therapy that is a small molecule CD38 inhibitor.
The teachings of Shoskes and as evidenced by Escande are discussed above.
It would have been prima facie obvious to combine the teachings of Jordan and Shoskes before the effective filing date of the claimed invention by substituting quercetin as taught by Shoskes to be the CD38-targeting therapy in the method for reducing the likelihood of antibody mediated rejection of an organ transplant in a subject that is resistant or has acquired resistance to immunosuppressive treatment as taught by Jordan to arrive at the claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to substitute quercetin as the CD38-targeting therapy because Shoskes teaches that quercetin administration can reduce transplant acute rejection incidence and as evidenced by Escande, quercetin is a CD38 inhibitor. One of ordinary skill in the art would have a reasonable expectation of success because Shoskes exemplified that quercetin can reduce transplant acute rejection incidence and Jordan teaches that CD38-targeting therapy can be used for reducing the likelihood of antibody mediated rejection (ABMR) of an organ transplant in a subject including wherein the subject is resistant or has acquired resistance to immunosuppressive treatment.
Conclusion
No claims allowed.
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/SAMANTHA LYNN SCHACHERMEYER/Examiner, Art Unit 1693 /SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693