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 .
Please note that the Examiner for this application has CHANGED.
Claims 1, 2, 5, 8, 12, 13, 16-19, 22, 23, 26, 28, 29, 31, 37, 40-42, and 46 are pending and under examination.
Information Disclosure Statement
The IDS statements filed on April 15, 2026 and 12/22/2025 have been considered by the examiner.
Claim Rejections - 35 USC § 112 - maintained
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, 2, 5, 8, 12, 13, 16-19, 22, 23, 26, 28, 29, 31, 37, 40, 41, 42, and 46 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claims contain 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.
With regard to Claims 1, 2, 5, 8, 12, 13, 16-19, 22, 23, 26, 28, 29, 31, 37, 40, 41, 42, and 46, the claims are directed to treating antibody-mediated rejection in a transplant recipient. The term "treating" is defined in the specification, and this definition includes absolute prevention of antibody-mediated rejection in a transplant recipient (see [0148]). Absolute prevention of AMR has not been shown to be possible in the prior art. For example, Henricksen et al. teach that no single protocol currently exists to address the complexities of treating patients with AMR (see page 7, paragraph 4, Henricksen, Erik et al. "Current State of Drug Therapies for Antibody-mediated Rejection After Heart Transplantation." The Canadian journal of cardiology, S0828-282X(25)01207-3 10 Oct. 2025; of record). Moreover, Matsuda et al. teach that long-lived plasma cells outlive conventional treatments, and they crucial role in the production of the antibodies that induce AMR (Matsuda, Yoshiko et al. "Approaches for Controlling Antibody- Mediated Allograft Rejection Through Targeting B Cells." Frontiers in immunology vol. 12 682334. 1 Jul. 2021; of record). Applicant does not address these cells and has not exemplified that the method of the instant application can prevent AMR via this conventional cause. Therefore, Applicant has not enabled one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Claims 1, 2, 5, 8, 12, 13, 16-19, 22, 23, 26, 28, 29, 31, 37, 40, 41, 42, and 46 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), 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, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
With regard to claims 1, 2, 5, 8, 12, 13, 16-19, 22, 23, 26, 28, 29, 31, 37, 40, 41, 42, and 46, the claims are directed to treating antibody-mediated rejection in a transplant recipient. The term "treating" is defined in the specification. The term "treating" included absolute prevention of antibody-mediated rejection in a transplant recipient (see [0148]). Absolute prevention of AMR has not been shown to be possible in the prior art. For example, Henricksen et al. teach that no single protocol currently exists to address the complexities of treating patients with AMR (see page 7, paragraph 4, Henricksen, Erik et al. "Current State of Drug Therapies for Antibody-mediated Rejection After Heart Transplantation." The Canadian journal of cardiology, S0828-282X(25)01207-3 10 Oct. 2025; of record). Moreover, Matsuda et al. teach that long-lived plasma cells outlive conventional treatments, and they crucial role in the production of the antibodies that induce AMR (Matsuda, Yoshiko et al. "Approaches for Controlling Antibody- Mediated Allograft Rejection Through Targeting B Cells." Frontiers in immunology vol. 12 682334. 1 Jul. 2021; of record). Applicant does not address these cells and thereby has not exemplified that the method of the instant application can prevent AMR via this conventional cause. As such, Applicant does not reasonably convey to one skilled in the relevant art that the inventor or joint inventors had possession of the claimed invention at the time the application was filed. This is on account of the fact that Applicant has not demonstrated that the claimed invention can prevent AMR. Here, the disclosure supports treating AMR or delaying or affecting the risk or timing of onset of AMR symptoms.
Response to Arguments
The Applicants’ response filed on April 15, 2026 has been fully considered but is unpersuasive. The applicants argue that the claims do not require absolute prevention. The applicants argue that the articles cited in the rejection, Hendricksen and Matsuda, disclose that treatments that are effective for particular patients may vary and may be effective but may not completely eliminate the disease in all cases. The applicants argue that the specification is enabled for methods of treating. However, this argument is unpersuasive because the substance of the rejection is that the specification is not enabled for the full scope of the claims, specifically for prevention. The applicants’ argument does not address the lack of enablement for prevention. As noted in the rejection, the term "treating" is defined in the specification, and this definition includes absolute prevention of antibody-mediated rejection in a transplant recipient (see [0148]). Absolute prevention of AMR has not been shown to be possible in the prior art. As presently written the claims do not exclude the embodiment of prevention as defined in the specification.
Regarding the applicants’ response to the rejection for lacking sufficient written description support, the applicants argue that the same reasons apply as above for enablement. The applicants argue that the scope of instant claims pertains to treatment. The applicants’ argument does not address the lack of enablement or written description support for prevention. As noted in the rejection, the term "treating" is defined in the specification, and this definition includes absolute prevention of antibody-mediated rejection in a transplant recipient (see [0148]). Absolute prevention of AMR has not been shown to be possible in the prior art. As presently written the claims do not exclude the embodiment of prevention as defined in the specification.
Claim Rejections - 35 USC § 103 - maintained
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.
Claims 1, 2, 5, 8, 12, 13, 16-19, 26, 29, 31, 37, 40-42, and 46 are rejected under 35 U.S.C. 103 as being unpatentable over Craig et al. (Craig, Timothy et al. "Treatment effect of switching from intravenous to subcutaneous C1-inhibitor for prevention of hereditary angioedema attacks: COMPACT subgroup findings." The journal of allergy and clinical immunology, vol. 7, 6 (2019): 2035-2038; of record) in view of Montgomery et al. (provided on the IDS filed 05/18/2023, Montgomery, R.A. et al., "Plasma-Derived C1 Esterase Inhibitor for Acute Antibody-Mediated Rejection Following Kidney Transplantation: Results of a Randomized Double-Blind Placebo-Controlled Pilot Study." The American Journal of Transplantation, vol. 16, 12, (2016): 3468-3478; of record), as evidenced by Fryar et al. with regard to the average weight of Americans (Fryar CD, Gu Q, Afful J, Carroll MD, Ogden CL. Anthropometric reference data for children and adults: United States, August 2021-August 2023. Vital Health Stat 3. 2025 Jun;(50): 1-28; of record).
Craig et al. teach a method of treating hereditary angioedema (HAE) attacks comprising a subject receiving human C1-INH according to a schedule comprising the following steps: a) intravenously received one or more iv-doses of C1-INH, then b) subcutaneously receiving C1-INH over at least 10 weeks, wherein each week at least one sc-dose is administered (see page 2035, paragraphs 3 and 4). Specifically, they teach the subcutaneous use of C1-INH over 16 weeks (see page 2035, paragraphs 3 and 4). Craig et al. teach that patients previously using C1-INH(IV) at various doses as routine prophylaxis can experience a substantial and clinically meaningful reduction in HAE attack rate when switching to C1- INH(SC) (see page 2037, paragraph 2). Craig et al. do not teach a method of treating antibody-mediated rejection in a transplant recipient.
Montgomery et al. teach a method of treating antibody-mediated rejection (AMR) in a transplant patient using an adapted method from treating HAE patients. Specifically, they used human plasma-derived C1-INH injections approved for use in patients with HAE at a higher dosing regimen than approved for HAE in order to treat acute AMR (see page 3469, paragraphs 3 and 4). Moreover, they used pharmacokinetic modeling from patients with HAE to inform the appropriate dosing patients with acute AMR (see page 3469, paragraph 7). The method of treating AMR included administering to the subject an intravenous infusion of 5000 U C1-INH (maximum of 100 U/kg) on day 1 followed by 2500 U C1-INH (maximum of 50 U/kg) on days 3, 5, 7, 9, 11, and 13 (see page 3469, paragraph 7). Compared to the control, the C1-INH group demonstrated a trend toward sustained improvement in renal function (see page 3468, Abstract). Here, Montgomery et al. adapt C1-INH treatments of HAE in order to treat AMR and find improvements in renal function for kidney transplant patients (see page 3468, Abstract).
This provides a clear motivation for using or modifying injection-based C1-INH treatments of HAE, like that of Craig et al., for use in patients with AMR.
Broadly, Montgomery et al. provide a motivation for adapting C1-INH injection treatments of HAE for use in AMR patients, and Craig et al. teach a method of treating HAE with C1-INH injections that has promising clinical results. Prior to the effective filing date of the instant application, Montgomery et al. had identified that adapting C1-INH treatments for HAE in order to treat AMR led to clinical improvements in AMR. In other words, it was well-known in the art that C1-INH HAE injection treatments could be adapted to treat AMR with a reasonable expectation of success. Given the motivation provided by Montgomery et al., it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant application to use or adapt a C1-INH injection-based method of treating HAE to the treatment of AMR with a reasonable expectation of success. In the same way, Craig et al. teach that patients saw significant improvements in HAE attack rate when receiving iv- doses followed by sc-doses, providing a motivation to adapt this method to treat AMR with a reasonable expectation of clinical improvements. In this case, it would have been obvious to one of ordinary skill in the art to combine the references of Craig et al. and Montgomery et al., particularly seeing as Montgomery et al. provides a clear motivation for using methods like that of Craig et al. in AMR patients.
With regard to claim 1, Craig et al. teach a method of treating hereditary angioedema (HAE) attacks comprising a recipient receiving human C1-INH according to a schedule comprising the following steps: a) intravenously receiving one or more iv-doses of C1-INH, then b) subcutaneously receiving C1- INH over 16 weeks, wherein each week two sc-doses are administered (see page 2035, paragraphs 3 and 4). As recited above, Craig et al. do not teach a method of treating antibody-mediated rejection in a transplant recipient. However, in light of Montgomery et al. and given the reasoning above, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant application to combine the references Craig et al. and Montgomery et al. to treat AMR.
With regard to claim 2, Craig et al. teach the method discussed above wherein the C1-INH is human C1-INH (see page 2035, paragraph 1). Again, given the reasoning above, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant application to combine the references to use the method of Craig et al. in treating AMR with human C1-INH.
With regard to claim 5, Craig et al. teach the method discussed above wherein in step b) the C1- INH was administered as an sc-dose of 40 to 180 IU/kg (see page 2035, paragraphs 3 and 4). Specifically, Craig et al. teach the use of 40 or 60 IU/kg for sc-dose. Montgomery et al. also teach the method discussed above wherein in step a) a maximum of 100 IU/kg were administered on day 1 followed by a maximum of 50 IU/kg on the remaining days (see page 3469, paragraph 7). Given the reasoning above, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant application to combine the references.
With regard to claim 8, Craig et al. teach the method discussed above wherein in step b) at least 10 sc-doses of C1-INH are administered (see page 2035, paragraph 3). Specifically, Craig et al. teach a twice-weekly administration of C1-INH for 16 weeks. Montgomery et al. also teach the method discussed above wherein in step a) at least two doses of C1-INH are administered over 2-21 days (see page 3469, paragraph 7). Specifically, Montgomery et al. teach dosing patients with an intravenous infusion of 5000 U C1 INH (maximum of 100 U/kg) or placebo on day 1 after the diagnosis of AMR, followed by 2500 U C1 INH (maximum of 50 U/kg) or placebo on days 3, 5, 7, 9, 11, and 13.
With regard to claim 12, Montgomery et al. teach the method discussed above wherein the iv- doses are administered every second day (see page 3469, paragraph 7).
With regard to claim 13, Montgomery et al. teach the method discussed above wherein in step a) a total of 20,000 units of C1-INH are administered intravenously over two weeks of doses every other day (see page 3477, paragraph 2).
With regard to claim 16, Craig et al. teach the method discussed above wherein in step b) at least 20 sc-doses of C1-INH are administered (see page 2035, paragraph 3). Specifically, Craig et al. teach a twice-weekly administration of C1-INH for 16 weeks.
With regard to claim 17, Montgomery et al. teach the method discussed above wherein the iv- doses over a period of 2 weeks (see page 3477, paragraph 2). Craig et al. teach the method discussed above wherein the sc-doses are administered over 16 weeks (see page 2035, paragraph 3). Given the reasoning discussed above, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant application to combine the two references to treat AMR. As such, the period of time during which sc-doses are administered is 8 times as long as the period of time during which iv-doses are administered.
With regard to claim 18, Montgomery et al. teach the method discussed above wherein 20,000 IU C1-INH is administered intravenously (see page 3474, paragraph 1), and Craig et al. teach the method discussed above wherein 32 doses of 40 to 60 IU/kg C1-INH are administered subcutaneously (see page 2035, paragraphs 3 and 4). Although the weights of the patients are not provided in the study by Craig et al., one of ordinary skill in the art would know that the average weight for US adults generally falls within the range of 75-95 kg and is generally above 40 kg, as according to Fryar et al., the average weight for men in the US is 90 kg (199.3 pounds) and 77.9 kg (171.8 pounds) for women (see page 2, paragraph 12). So, generally, the total amount of C1-INH administered subcutaneously is around 98,560 IU (77 kg * 40 IU/kg * 32 doses), which is higher than twice the amount of C1-INH administered intravenously, 40,000 IU (20,000 IU * 2). This estimate is conservative, as it uses the average weight for women in the US and the lowest dosage taught in Craig et al. Again, given the reasoning above, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant application to combine the references.
With regard to claim 19, Craig et al. teach the method discussed above wherein, although the weights of the patients are not provided in the study, one of ordinary skill in the art would know that the average weight for US adults generally falls within the range of 75-95 kg, as shown by Fryan et al. So, generally, the total amount of C1-INH administered subcutaneously is around 98,560 IU (77 kg * 40 IU/kg * 32 doses), using the same estimate provided above (see page 2035, paragraphs 3 and 4).
With regard to claim 26, Montgomery et al. teach the method discussed above wherein the transplant recipient is a kidney transplant recipient (see Title).
With regard to claim 29, Montgomery et al. teach the method discussed above wherein the subject had previously been treated with IVIg with or without plasmapheresis (see paragraph 7, Treatment and sample collection).
With regard to claim 31, Montgomery et al. teach the method discussed above wherein the method is initiated 90-365 days after transplantation (see Table 2, Day since current transplant).
With regard to claim 37, Montgomery et al. teach the method discussed above wherein 100 mg doses of IVIg/kg are used in addition to the administration of C1-INH (see page 3469, paragraph 7, Treatment and sample collection).
With regard to claim 40, Montgomery et al. teach the method of treating antibody-mediated rejection in an allograft transplantation recipient discussed above comprising intravenously administering 7 doses of C1-INH to the recipient over two weeks wherein the doses contain a maximum of 50 IU/kg C1-INH (see page 3469, paragraph 7, Treatment and sample collection). Craig et al. teach the method of treating HAE discussed above comprising administering 32 sc-doses of 40 to 60 IU/kg C1-INH to the recipient twice weekly over 16 weeks (see page 2035, paragraphs 3 and 4). Given the reasoning discussed above, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant application to combine the two references to treat AMR.
With regard to claims 41 and 42, Montgomery et al. teach the method of treating antibody- mediated rejection in an allograft transplantation recipient discussed above comprising intravenous administration of an initial infusion of 5000 U of C1 INH followed by 2500 U of C1 INH every other day for 2 weeks (20,000 units over 13 days) (see page 3469, paragraph 7, Treatment and sample collection, and page 3474, paragraph 1). Craig et al. teach the method of treating HAE discussed above comprising administering 32 sc-doses of 40 to 60 IU/kg C1-INH to the recipient twice weekly over 16 weeks (see page 2035, paragraphs 3 and 4). As discussed above, although the weights of the patients are not provided in the study by Craig et al., one of ordinary skill in the art would know that the average weight for US adults generally falls within the range of 75-95 kg, as discussed above. So, the dosage of C1-INH administered subcutaneously ranges from 3,000 IU (75 kg * 40 IU/kg) to 5,700 IU (95 kg * 60 IU/kg), and the total amount of C1-INH administered subcutaneously ranges from 96,000 IU (75 kg * 40 IU/kg * 32 doses) to 182,400 IU (95 kg * 60 IU/kg * 32 doses). Given the reasoning discussed above, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant application to combine the two references to treat AMR.
With regard to claim 46, Craig et al. teach the method discussed above comprising subcutaneously administering C1-INH over 16 weeks wherein doses are administered twice weekly (see page 2035, paragraphs 3 and 4).
Response to Arguments
The Applicants’ response filed on April 15, 2026 has been fully considered but is unpersuasive. The applicants argue that Montgomery does not provide a motivation to combine its teachings with those of Craig; “nor does the combination of Montgomery with Craig provide a reasonable expectation of success”. Specifically, the applicants argue that Montgomery teaches high-dose intravenous regimen administered over about 13 days for treatment of acute AMR which “is quite distinct from the claimed methods, which require prolonged subcutaneous administration over at least 10 weeks”.
However, this argument is unpersuasive because in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). While Montgomery teaches high-dose intravenous regiment, Craig teaches a dosing regimen of C1-INH involving initial intravenous administration followed by subcutaneous dosing over a 16 week period for treating HAE. Further, in response to applicant's argument that there was no motivation to combine the references, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). Further, the applicants’ argument regarding the Montgomery reference does not show significant clinical results based on the Phase III clinical trial of NCT02547220, a prior art reference is available for all that it teaches. Montgomery et al. teach the method of treating antibody- mediated rejection in an allograft transplantation recipient discussed above comprising intravenous administration of an initial infusion of 5000 U of C1 INH followed by 2500 U of C1 INH every other day for 2 weeks (20,000 units over 13 days) (see page 3469, paragraph 7, Treatment and sample collection, and page 3474, paragraph 1). Montgomery et al. teach the method discussed above wherein 100 mg doses of IVIg/kg are used in addition to the administration of C1-INH (see page 3469, paragraph 7, Treatment and sample collection).
In addition, regarding the argument regarding no reasonable expectation of success and unexpected results, the arguments of counsel can not take the place of evidence on the record. Further, the examples provided in the argument for producing such unexpected results are not commensurate with the scope of the present claims.
Claims 1, 22, and 23 stand rejected under 35 U.S.C. 103 as being unpatentable over Craig et al. (Craig, Timothy et al. "Treatment effect of switching from intravenous to subcutaneous C1-inhibitor for prevention of hereditary angioedema attacks: COMPACT subgroup findings." The journal of allergy and clinical immunology, vol. 7, 6 (2019): 2035-2038) in view of Montgomery et al. (provided on the IDS filed 05/18/2023, Montgomery, R.A. et al., "Plasma-Derived C1 Esterase Inhibitor for Acute Antibody- Mediated Rejection Following Kidney Transplantation: Results of a Randomized Double-Blind Placebo- Controlled Pilot Study." The American Journal of Transplantation, vol. 16, 12, (2016): 3468-3478), as evidenced by Fryar et al. with regard to the average weight of Americans (Fryar CD, Gu Q, Afful J, Carroll MD, Ogden CL. Anthropometric reference data for children and adults: United States, August 2021- August 2023. Vital Health Stat 3. 2025 Jun;(50): 1-28).as applied to claim 1 above, and further in view of Metzner et al. (provided on the IDS submitted 05/18/2023, Document ID: US20190175683, published 06/13/2019).
Craig et al. and Montgomery et al. teach the methods discussed above and applied to claims 1, 2, 5, 8, 12, 13, 16-19, 26, 29, 31, 37, 40-42, and 46. They do not, however, teach the method wherein each iv-dose comprises the same amount of C1-INH and the C1-INH dose is administered at a concentration of 200 to 800 IU/mL.
Metzner et al. teach pharmaceutical formulations and uses of C1-INH for use in treating HAE and in preventing rejection of transplanted tissue in a kidney transplant recipient patient (see [0039], [0017]). Further, Metzner et al. teach the use of subcutaneous or intravenous injections of C1-INH to treat the conditions, and they teach an efficient mode of operation for the treatment by standardizing its use in a kit (see [0014], [0161]). In other words, their method is pharmaceutically and therapeutically efficient because it allows for high concentrations of C1-INH and has an increased C1-INH stability (see [0013]).
With regard to Craig et al. and Montgomery et al., Metzner et al. teach the use of intravenous and subcutaneous injections of C1-INH for treatment of the same patient population as Craig et al. and Montgomery et al., as Metzner et al. teach the treatment of patients with HAE and transplant patients with AMR after organ transplantation (see [0014], [0039]). Here, Metzner teach the same method of treatment, C1-INH injection, for the same groups of patients as compared to Craig et al. and Montgomery et al., and Metzner also show that their teachings provide benefits including increased stability of the C-INH (see Abstract, [0013]). Given the fact that they use the same medication to treat the same patient populations and each demonstrate promising clinical or practical benefits, Metzner et al. provide a motivation to combine the references in the treatment C1-INH-related conditions. As such, it would have been obvious a person of ordinary skill in the art prior to the effective filing date of the instant application to combine the teachings of the references.
With regard to claim 22, Metzner et al. teach the method discussed above wherein each iv-dose comprises the same amount of C1-INH as each sc-dose (see [0014], [0038]). Metzner et al. further teach that patients can self-administer the provided formulations either intravenously or subcutaneously (see [0151], [0152]), and that the provided formulations exhibit a high local tolerance both for subcutaneous and intravenous administration (see [0154]). As such, Metzner et al. provide a motivation for use of these formulations in both subcutaneous and intravenous injections because they provide both practical and clinical benefits. Given the reasoning above, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant application to combine the references.
With regard to claim 23, Metzner et al. teach the method discussed above wherein the C1-INH is administered intravenously or subcutaneously at a concentration of about 400-2,000 IU/mL, preferably about 500 IU/mL (see [0079]). At this concentration, about 500 IU/mL, Metzner et al. observed long term stability for the pharmaceutical composition, providing a clear motivation to use said concentration, seeing as it provides practical benefits (see [0204]). Given this and the reasoning above, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant application to combine the references and use a concentration of C1-INH at 500 IU/mL in order to improve stability of the composition. Although Metzner et al. explicitly teach a motivation for using a concentration of about 500 IU/mL, they do not teach the entire range claimed in claim 23 of the instant application. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Geisler, 116 F.3d 1465, 1469-71, 43 USPQ2d 1362, 1365- 66 (Fed. Cir. 1997) (Claim reciting thickness of a protective layer as falling within a range of "50 to 100 Angstroms" considered prima facie obvious in view of prior art reference teaching that "for suitable protection, the thickness of the protective layer should be not less than about 10 nm [i.e., 100 Angstroms]." The court stated that "by stating that 'suitable protection' is provided if the protective layer is 'about' 100 Angstroms thick, [the prior art reference] directly teaches the use of a thickness within [applicant's] claimed range."). Here, Metzner et al. state that increased long term stability is provided if the concentration is about 500 IU/mL (see [0204]), which, based on the caselaw provided above in Geisler, thereby teaches the use of the concentration in Applicant's claimed range of 200 IU/mL to 800 IU/mL.
Response to Arguments
The Applicants’ response filed on April 15, 2026 has been fully considered but is unpersuasive. The applicants argue that Montgomery does not provide a motivation to combine its teachings with those of Craig; “nor does the combination of Montgomery with Craig provide a reasonable expectation of success”. Specifically, the applicants argue that Montgomery teaches high-dose intravenous regimen administered over about 13 days for treatment of acute AMR which “is quite distinct from the claimed methods, which require prolonged subcutaneous administration over at least 10 weeks”. Further, the applicants argue that Fryar nor Metzner are remedial.
However, this argument is unpersuasive because in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). While Montgomery teaches high-dose intravenous regiment, Craig teaches a dosing regimen of C1-INH involving initial intravenous administration followed by subcutaneous dosing over a 16 week period for treating HAE. Further, in response to applicant's argument that there was no motivation to combine the references, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). Further, the applicants’ argument regarding the Montgomery reference does not show significant clinical results based on the Phase III clinical trial of NCT02547220, a prior art reference is available for all that it teaches. Montgomery et al. teach the method of treating antibody- mediated rejection in an allograft transplantation recipient discussed above comprising intravenous administration of an initial infusion of 5000 U of C1 INH followed by 2500 U of C1 INH every other day for 2 weeks (20,000 units over 13 days) (see page 3469, paragraph 7, Treatment and sample collection, and page 3474, paragraph 1). Montgomery et al. teach the method discussed above wherein 100 mg doses of IVIg/kg are used in addition to the administration of C1-INH (see page 3469, paragraph 7, Treatment and sample collection).
In addition, regarding the argument regarding no reasonable expectation of success and unexpected results, the arguments of counsel can not take the place of evidence on the record. Further, the examples provided in the argument from the instant specification for producing such unexpected results are not commensurate with the scope of the present claims.
Claims 1, 26, and 28 stand rejected under 35 U.S.C. 103 as being unpatentable over Craig et al. (Craig, Timothy et al. "Treatment effect of switching from intravenous to subcutaneous C1-inhibitor for prevention of hereditary angioedema attacks: COMPACT subgroup findings." The journal of allergy and clinical immunology, vol. 7, 6 (2019): 2035-2038; of record) in view of Viglietti et al. (provided on the IDS submitted 05/18/2023, Viglietti, D et al. "C1 Inhibitor in Acute Antibody-Mediated Rejection Nonresponsive to Conventional Therapy in Kidney Transplant Recipients: A Pilot Study." American journal of transplantation: official journal of the American Society of Transplantation and the American Society of Transplant Surgeons vol. 16,5 (2016)).
Craig et al. teach the method discussed and applied above. Specifically, Craig et al. teach a method of treating hereditary angioedema (HAE) attacks comprising a subject receiving human C1-INH according to a schedule comprising the following steps: a) intravenously received one or more iv-doses of C1-INH, then b) subcutaneously receiving C1-INH over at least 10 weeks, wherein each week at least one sc-dose is administered (see page 2035, paragraphs 3 and 4). Specifically, they teach the subcutaneous use of C1-INH over 16 weeks (see page 2035, paragraphs 3 and 4). Craig et al. teach that patients previously using C1-INH(IV) at various doses as routine prophylaxis can experience a substantial and clinically meaningful reduction in HAE attack rate when switching to C1-INH(SC) (see page 2037, paragraph 2). Craig et al. do not teach a method of treating antibody-mediated rejection in a transplant recipient.
Viglietti et al. teach a method of treating AMR in a transplant patient using an adapted method from treating HAE patients (see page 1597, paragraph 4). Viglietti et al. teach the use of intravenously injected C1-INH added to high-dose IVIG for the treatment of acute AMR that is nonresponsive to conventional antibody-targeting therapies in kidney transplant recipients (see page 1597, paragraph 4). Viglietti explicitly state that the C1-INH they use in the study is approved for the treatment of acute abdominal or facial attacks of HAE and that in the field of transplantation, experimental data showed that C1-INH prevents acute AMR in baboons (see page 1597, paragraph 3). This provided the motivation for their study, in which they adapt the use of C1-INH intravenous injections, which is a treatment for HAE, to treat AMR, as they have a reasonable expectation of success given promising results in baboons (see page 1597, paragraphs 3 and 4). Here, Viglietti et al. adapt C1-INH intravenous injection treatments of HAE in order to treat AMR and find a significant improvement in allograft function and a decrease in complement C1q-binding capacity of anti-HLA DSA together with reduced C4d deposition in allograft capillaries in kidney transplant patients (see page 1600, paragraph 5). This provides a clear motivation for using or modifying injection-based C1-INH treatments of HAE, like that of Craig et al., for use in patients with AMR.
Broadly, Viglietti et al. provide a motivation for adapting C1-INH injection treatments of HAE for use in AMR patients, and Craig et al. teach a method of treating HAE with C1-INH injections that has promising clinical results. Prior to the effective filing date of the instant application, Viglietti et al. had identified that adapting C1-INH treatments for HAE in order to treat AMR led to clinical improvements in AMR. In other words, it was well-known in the art that C1-INH HAE injection treatments designed for treating HAE could be adapted to treat AMR with a reasonable expectation of success. Given the motivation provided by Viglietti et al., it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant application to use or adapt a C1-INH injection-based method of treating HAE to the treatment of AMR with a reasonable expectation of success. In this case, it would have been obvious to one of ordinary skill in the art to combine the references of Craig et al. and Viglietti et al., seeing as Viglietti et al. provides a clear motivation for using methods like that of Craig et al. in AMR patients.
With regard to claim 1, as discussed above, Craig et al. teach a method of treating HAE attacks comprising a recipient receiving human C1-INH according to a schedule comprising the following steps: a) intravenously received one or more iv-doses of C1-INH, then b) subcutaneously receiving C1-INH over 16 weeks, wherein each week two sc-doses are administered (see page 2035, paragraph 4). As recited above, Craig et al. do not teach a method of treating antibody-mediated rejection in a transplant recipient. Given the reasoning above, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant application to combine the references and use the method of Craig et al. to treat AMR.
With regard to claim 26, Viglietti et al. teach the method discussed above wherein the transplant recipient is a kidney transplant recipient (see Title). Given the reasoning above, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant application to combine the references.
With regard to claim 28, Viglietti et al. teach the method discussed above wherein the recipient is a kidney transplant recipient and is refractory to treatment with IVIg with plasmapheresis (see page 1600, paragraph 6). Specifically, Viglietti et al. teach a method of administering C1-INH in treating acute AMR wherein the recipient is a kidney transplant recipient and is nonresponsive to conventional therapy, consisting of plasmaphereses, rituximab, and high-dose IVIG (see page 1600, paragraph 6). Given the reasoning above, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant application to combine the references.
Response to Arguments
The Applicants’ response filed on April 15, 2026 has been fully considered but is unpersuasive. The applicants argue that Viglietti et al does not provide a motivation to combine its teachings with those of Craig; nor does the combination of Viglietti et al with Craig provide a reasonable expectation of success. Specifically, the applicants argue that Viglietti et al does not disclose or suggest any subcutaneous administration.
However, this argument is unpersuasive because in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). While Viglietti et al. teach a method of administering C1-INH in treating acute AMR wherein the recipient is a kidney transplant recipient and is nonresponsive to conventional therapy, consisting of plasmaphereses, rituximab, and high-dose IVIG (see page 1600, paragraph 6), Craig teaches a dosing regimen of C1-INH involving initial intravenous administration followed by subcutaneous dosing over a 16 week period for treating HAE. Further, in response to applicant's argument that there was no motivation to combine the references, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). In addition, regarding the argument regarding no reasonable expectation of success, the arguments of counsel cannot take the place of evidence on the record.
Double Patenting - maintained
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, 2, 5, 8, 12, 13, 16-19, 26, 28, 29, 31, 37, 40-42, and 46 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-27 of U.S. Patent No. 9895428 (provided on the IDS submitted 05/18/2023), hereinafter Broom et al., in view of Craig et al. (Craig, Timothy et al. "Treatment effect of switching from intravenous to subcutaneous C1-inhibitor for prevention of hereditary angioedema attacks: COMPACT subgroup findings." The journal of allergy and clinical immunology, vol. 7, 6 (2019): 2035-2038), as evidenced by Fryar et al. (Fryar CD, Gu Q, Afful J, Carroll MD, Ogden CL. Anthropometric reference data for children and adults: United States, August 2021-August 2023. Vital Health Stat 3. 2025 Jun;(50): 1-28) and Viglietti et al. (provided on the IDS submitted 05/18/2023, Viglietti, D et al. "C1 Inhibitor in Acute Antibody-Mediated Rejection Nonresponsive to Conventional Therapy in Kidney Transplant Recipients: A Pilot Study." American journal of transplantation: official journal of the American Society of Transplantation and the American Society of Transplant Surgeons vol. 16,5 (2016)).
Broom et al. claim a method for treating or preventing antibody-mediated rejection of a transplanted organ comprising administering a C1-INH protein (see claims 1 and 14). Specifically, Broom et al. claim a method of treating AMR of a kidney allograft in a patient in need thereof, the method comprising administration of a C1-INH protein at a dose of about 20,000 units given in divided doses over a duration of about 1 to 30 days, wherein the administration is initiated within 1 to 90 days of organ transplantation, treatment with plasmapheresis, treatment with IVIg, or diagnosis of AMR of the patient, wherein the method results in a therapeutic effect lasting for at least 3 months after cessation of therapy (see claim 14). Broom et al. do not, however, teach the administration of iv-doses of C1-INH followed by the administration of sc-doses of C1-INH over at least 10 weeks.
Craig et al. teach a method of treating HAE comprising the patient first receiving iv-doses followed by sc-doses (see page 2035, paragraphs 3 and 4). Craig et al. teach a method of treating HAE attacks comprising a subject receiving human C1-INH according to a schedule comprising the following steps: a) intravenously received one or more iv-doses of C1-INH, then b) subcutaneously receiving C1- INH over at least 10 weeks, wherein each week at least one sc-dose is administered (see page 2035, paragraphs 3 and 4). Specifically, they teach the subcutaneous use of C1-INH over 16 weeks (see page 2035, paragraphs 3 and 4). Craig et al. teach that patients previously using C1-INH(IV) at various doses as routine prophylaxis can experience a substantial and clinically meaningful reduction in HAE attack rate when switching to C1-INH(SC) (see page 2037, paragraph 2). Craig et al. do not teach a method of treating antibody-mediated rejection in a transplant recipient.
Although Broom et al. do not explicitly claim the schedule of administration recited in Craig et al., there existed a clear motivation for the combination of the references in the art prior to the effective filing date of the instant application. Specifically, Viglietti et al. teach a motivation for adapting C1-INH treatments of HAE for use in treating AMR. Viglietti et al. teach a method of treating AMR in a transplant patient using an adapted method from treating HAE patients (see page 1597, paragraph 4). Viglietti et al. teach the use of intravenously injected C1-INH added to high-dose IVIG for the treatment of acute AMR that is nonresponsive to conventional antibody-targeting therapies in kidney transplant recipients (see page 1597, paragraph 4). Viglietti explicitly state that the C1-INH they use in the study is approved for the treatment of acute abdominal or facial attacks of HAE and that in the field of transplantation, experimental data showed that C1-INH prevents acute AMR in baboons (see page 1597, paragraph 3). This provided the motivation for their study, in which they adapt the use of C1-INH intravenous injections, which is a treatment for HAE, to treat AMR, as they have a reasonable expectation of success given promising results in baboons (see page 1597, paragraphs 3 and 4). Here, Viglietti et al. adapt C1- INH intravenous injection treatments of HAE in order to treat AMR and find a significant improvement in allograft function and a decrease in complement C1q-binding capacity of anti-HLA DSA together with reduced C4d deposition in allograft capillaries in kidney transplant patients (see page 1600, paragraph 5). This provides a clear motivation for using or modifying injection-based C1-INH treatments of HAE, like that of Craig et al., for use in patients with AMR.
Broadly, Viglietti et al. provide a motivation for adapting C1-INH injection treatments of HAE for use in AMR patients, and Craig et al. teach a method of treating HAE with C1-INH injections that has promising clinical results. Prior to the effective filing date of the instant application, Viglietti et al. had identified that adapting C1-INH treatments for HAE in order to treat AMR led to clinical improvements in AMR. In other words, it was well-known in the art that C1-INH HAE injection treatments designed for treating HAE could be adapted to treat AMR with a reasonable expectation of success. Given the motivation provided by Viglietti et al., it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant application to use or adapt a C1-INH injection-based method of treating HAE to the treatment of AMR with a reasonable expectation of success. In this case, it would have been obvious to one of ordinary skill in the art to combine the references of Broom et al. and Craig et al., seeing as Viglietti et al. provides a clear motivation for adapting methods of treating AMR like those recited in Broom et al. using methods like that of Craig et al. Given this motivation, one of ordinary skill in the art would have a reasonable expectation of success in using methods of treating HAE to treat AMR according to the schedule recited in Craig et al. Further, Viglietti et al. and Broom et al. use the same medication, C1-INH, to treat the same patient population, kidney transplant patients with AMR. Given the fact that they treat the same patient population with the same medication, a person having ordinary skill prior to the effective filing date of the instant application would have been motivated to combine the references.
With regard to claim 1 of the instant application, Broom et al. claim a method of treating AMR in kidney allograft in a patient in need thereof, the method comprising administration of a C1-INH protein at a dose of about 20,000 units given in divided doses over a duration of about 1 to 30 days, wherein the administration is initiated within 1 to 90 days of organ transplantation, treatment with plasmapheresis, treatment with IVIg, or diagnosis of AMR of the patient, wherein the method results in a therapeutic effect lasting for at least 3 months after cessation of therapy (see claim 14). Though the scope of claim 1 of Broom et al. broadly encompasses the specific schedule of claim 1 of the instant application, Broom et al. do not distinctly claim said schedule. Craig et al. do, however, teach that patients receive iv-doses followed by sc-doses. Specifically, they teach a method of treating HAE attacks comprising a recipient receiving human C1-INH according to a schedule comprising the following steps: a) intravenously received one or more iv-doses of C1-INH, then b) subcutaneously receiving C1-INH over 16 weeks, wherein each week two sc-doses are administered (see page 2035, paragraph 4). Given the reasoning provided above, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant application to combine the references of Broom et al. and Craig et al. to treat AMR with a reasonable expectation of success, given the motivation provided by Viglietti et al.
With regard to claim 2, Broom et al. claim the use of C1-INH to treat AMR in kidney transplant patients in claims 1-25. Although the broad scope of claims 1-25 of Broom et al. encompass the use of human C1-INH, Broom et al. do not explicitly claim the use of human C1-INH. Viglietti et al. do, however, teach the use of human C1-INH in treating the same condition, AMR following a kidney transplantation (see page 1597, paragraph 3). Given the reasoning to combine references provided above, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant application to use human C1-INH.
With regard to claim 5, Broom et al. claim the method of use of C1-INH in claims 1-25 discussed above, but they do not explicitly claim the dosage or method of administration for the medication. Specifically, Broom et al. do not explicitly claim that the C1-INH is administered at an iv-dose or sc-dose of 40-180 IU/kg. Craig et al. teach the method discussed above wherein in step b) the C1-INH was administered as an sc-dose of 40 to 180 IU/kg (see page 2035, paragraphs 3 and 4). Specifically, Craig et al. teach the use of 40 or 60 IU/kg for sc-dose. Given the reasoning provided above, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant application to combine the references of Broom et al. and Craig et al. to treat AMR using the schedule and dosing of Craig et al.
With regard to claim 8, Broom et al. teach the method discussed above wherein C1-INH is administered at a total dose of 20,000 U given in divided doses over about 1 to 30 days (see claims 1, 14), specifically over 13 days (see claims 11, 25). Broom et al. do not, however, claim the specific method of administration as iv-doses or sc-doses. As discussed above, Craig et al. teaches the use of iv- doses followed by sc-doses (see page 2035, paragraphs 3 and 4). In particular, they teach the use of 32 sc-doses over 16 weeks (see page 2035, paragraphs 3 and 4). Given the reasoning above, it would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instant application to combine the references of Broom et al. and Craig et al. to treat AMR with 32 sc-doses with a reasonable expectation of success.
With regard to claim 12, Broom et al. teach the method discussed above wherein C1-INH is administered at a total dose of 20,000 U given in divided doses over about 1 to 30 days (see claims 1, 14), specifically over 13 days (see claims 11, 25). Broom et al. do not, however, claim the specific method of administration as iv-doses every second, third, or fourth day. Viglietti et al. do teach the use of iv-doses of C1-INH in treating AMR in kidney patients, and they teach iv administration twice weekly (see page 1597, paragraph 11). Given the fact that Viglietti et al. and Broom et al. teach the same patient population with the same medication, C1-INH, and provided the reasoning recited above, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant application to combine the references of Viglietti et al. and Broom et al. to treat AMR with iv-doses of C1-INH.
With regard to claim 13, Broom et al. teach the method discussed above wherein C1-INH is administered at a total dose of 20,000 U given in divided doses over about 1 to 30 days (see claim 1), Although Broom et al. do not explicitly claim the administration of 7,000 to 36,000 IU C1-INH intravenously or 4,000 to 15,000 IU C1-INH administered weekly subcutaneously, they do claim that 20,000 IU of C1-INH are administered in divided doses. Moreover, as discussed above, although Broom et al. do not explicitly teach the method of administration, it would have been obvious to a person of ordinary skill prior to the effective filing date of the instant application to use 20,000 IU of iv-doses on account of the motivation provided by Viglietti et al.
With regard to claim 16, Broom et al. claim the method discussed above, wherein C1-INH protein at a dose of about 20,000 units are in divided doses over a duration of about 1 to 30 days (see claims 1, 14). Broom et al. do not, however, explicitly claim the use of sc-doses. Craig et al. teach the method discussed above wherein in step b) at least 20 sc-doses of C1-INH are administered (see page 2035, paragraph 3). Specifically, Craig et al. teach a twice-weekly administration of C1-INH for 16 weeks (for a total of 32 sc-doses). Given the reasoning provided above, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant application to combine the references of Broom et al. and Craig et al. to treat AMR using at least 20 sc-doses of C1-INH.
With regard to claim 17, Broom et al. claim the method discussed above wherein the doses are administered over a period of 13 days (claims 1, 11, 14, and 25). As discussed above, Viglietti et al. teach a method of treating AMR in kidney transplant patients with iv injections of C1-INH (see page 1597, paragraph 11). Given the fact that Viglietti et al. and Broom et al. teach the same patient population with the same medication, C1-INH, and provided the reasoning recited above, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant application to combine the references of Viglietti et al. and Broom et al. to treat AMR with iv-doses of C1-INH. Craig et al. teach the method discussed above wherein the sc-doses are administered over 16 weeks (see page 2035, paragraph 3). Given the reasoning discussed above, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant application to combine Craig et al. and Broom et al. to treat AMR according to the schedule of Craig et al. As such, in the combined references the period of time during which sc-doses are administered is 16 weeks, over 8 times as long as the period of time during which iv-doses are administered, 13 days.
With regard to claim 18, Broom et al. teach the method discussed above wherein 20,000 IU C1- INH is administered to a subject with AMR. As discussed above, given the teachings of Viglietti et al., it would have been obvious to one of ordinary skill prior to the effective filing date of the instant application to use the method of Broom et al. with intravenous injections to treat AMR in kidney transplant patients. Further, Craig et al. teach the method discussed above wherein 32 doses of 40 to 60 IU/kg C1-INH are administered subcutaneously (see page 2035, paragraphs 3 and 4). Although the weights of the patients are not provided in the study by Craig et al., one of ordinary skill in the art would know that the average weight for US adults generally falls within the range of 75-95 kg and is generally above 40 kg, as according to Fryar et al., the average weight for men in the US is 90 kg (199.3 pounds) and 77.9 kg (171.8 pounds) (see page 2, paragraph 12). So, generally, the total amount of C1-INH administered subcutaneously is 98,560 IU (77 kg * 40 IU/kg * 32 doses), which is higher than twice the amount of C1-INH administered intravenously, 40,000 IU (20,000 IU * 2) (see page 2035, paragraph 3 and 4). Given the reasoning discussed above, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant application to combine the two references to treat AMR. As such, in the combined references the amount of C1-INH administered subcutaneously is more than twice that administered intravenously.
With regard to claim 19, Broom et al. claim the method discussed above wherein 20,000 IU C1- INH is administered to a patient (see claims 1, 14). Craig et al. teach the method discussed above wherein, although the weights of the patients are not provided in the study by Craig et al., one of ordinary skill in the art would know that the average weight for US adults generally falls within the range of 75-95 kg and is generally above 40 kg, as according to Fryar et al., the average weight for men in the US is 90 kg (199.3 pounds) and 77.9 kg (171.8 pounds) (see page 2, paragraph 12). So, generally, the total amount of C1-INH administered subcutaneously 98,560 IU (77 kg * 40 IU/kg * 32 doses) (see page 2035, paragraph 3 and 4). Given the reasoning discussed above, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant application to combine the two references to treat AMR. As such, in the combined references the total amount of C1-INH administered subcutaneously is more than 50,000 IU.
With regard to claim 26, Broom et al. claim the method discussed above wherein the transplant recipient is a kidney transplant recipient (claims 7, 8, and 14-27).
With regard to claim 28, Broom et al. claim the method discussed above (see claims 1, 14), but do not teach the method wherein the kidney transplant recipient has one or more of the following characteristics: a) has a post-transplant eGFR greater than or equal to 40 mL/min/1.73m² within 60 days of transplant; b) has a 50% increase in urine output; c) has a 50% decrease in serum creatinine during the first 7 days post-transplant; or d) is refractory to treatment with IVIg with or without plasmapheresis. Viglietti et al. teach the method discussed above wherein the recipient is a kidney transplant recipient and is refractory to treatment with IVIg with plasmapheresis. Specifically, Viglietti et al. teach a method of administering C1-INH in treating acute AMR wherein the recipient is a kidney transplant recipient and is nonresponsive to conventional therapy, consisting of plasmaphereses, rituximab, and high-dose IVIG (see page 1600, paragraph 6). Again, given the reasoning discussed above, it would have been obvious to one of ordinary skill prior to the effective filing date of the instant application to combine the references.
With regard to claim 29, Broom et al. claim the method discussed above (see claims 1 and 14) wherein the method is initiated within 1 to 90 days of organ transplantation, treatment with plasmapheresis, treatment with intravenous immunoglobulin (IVIg), or diagnosis of AMR of the patient, wherein the method results in a therapeutic effect lasting for at least 3 months after cessation of therapy (see claims 1, 14). Seeing as Broom et al. claim that their method of treating AMR with C1-INH begins within 90 days of treatment with IVIg or plasmapheresis, Broom et al. claim that the patient population includes those who have previously been treated with IVIg or plasmapheresis.
With regard to claim 31, Broom et al. claim the method discussed above (see claims 1 and 14) wherein the method is initiated within 1 to 90 days of organ transplantation, treatment with plasmapheresis, treatment with intravenous immunoglobulin (IVIg), or diagnosis of AMR of the patient, wherein the method results in a therapeutic effect lasting for at least 3 months after cessation of therapy (see claims 1, 14). Seeing as diagnosis with AMR occurs after transplantation, the claimed patient population includes patients who underwent transplantation, were later diagnosed with AMR, and began treatment 90 days after the diagnosis, thereby beginning treatment more than 3 months after transplantation.
With regard to claim 37, Broom et al. teach the method discussed above wherein intravenous immunoglobulin (IVIg) is used in addition to the administration of C1-INH (see claims 1, 4, 14, and 18).
With regard to claim 40, Broom et al. teach the method of treating antibody-mediated rejection in a kidney transplantation recipient discussed above comprising administration of a C1-INH protein at a dose of about 20,000 units given in divided doses over a duration of about 1 to 30 days, wherein the administration is initiated within 1 to 90 days of organ transplantation, treatment with plasmapheresis, treatment with intravenous immunoglobulin (IVIg), or diagnosis of AMR of the patient, wherein the method results in a therapeutic effect lasting for at least 3 months after cessation of therapy (see claim 14). Specifically, Broom et al. claim the administration of the C1-INH over 13 days (see claims 11, 25). Broom et al. do not, however, explicitly claim the administration of the drug 3-10 times at doses of 40 to 120 IU/kg. Craig et al do teach the administration of the drug at a dose of 40-60 IU/kg, and they also teach that the patients receive iv-doses of C1-INH. Given the reasoning discussed above, it would have been obvious to one of ordinary skill prior to the effective filing date of the instant application to combine the references to teach the treatment of AMR according to the schedule recited in Craig et al. wherein the patient receives iv-doses according to the method of Broom et al. Craig et al. also teach the method of treating HAE discussed above comprising administering 32 sc-doses of 40 to 60 IU/kg C1-INH to the recipient twice weekly over 16 weeks. Given the reasoning discussed above, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant application to combine the two references to treat AMR.
With regard to claim 41, Broom et al. teach the method of treating antibody-mediated rejection in a kidney transplantation recipient discussed above comprising administration of a C1-INH protein at a dose of about 20,000 units given in divided doses over a duration of about 1 to 30 days, wherein the administration is initiated within 1 to 90 days of organ transplantation, treatment with plasmapheresis, treatment with intravenous immunoglobulin (IVIg), or diagnosis of AMR of the patient, wherein the method results in a therapeutic effect lasting for at least 3 months after cessation of therapy (see claim 14). Specifically, Broom et al. claim the administration of the C1-INH over 13 days (see claims 11, 25). Broom et al. do not, however, explicitly claim the administration of the drug 3-10 times at doses of 2,500-8,500 IU. Craig et al. do teach the administration of the drug at a dose of 40-60 IU/kg, and they also teach that the patients receive iv-doses of C1-INH. Given the reasoning discussed above, it would have been obvious to one of ordinary skill prior to the effective filing date of the instant application to combine the references to teach the treatment of AMR according to the schedule recited in Craig et al. wherein the patient receives iv-doses according to the method of Broom et al. Craig et al. also teach the method of treating HAE discussed above comprising administering 32 sc-doses of 40 to 60 IU/kg C1-INH to the recipient twice weekly over 16 weeks. As discussed above, although the weights of the patients are not provided in the study by Craig et al., one of ordinary skill in the art would know that the average weight for US adults generally falls within the range of 75-95 kg, as evidenced by Fryan et al. So, the dosage of C1-INH administered subcutaneously ranges from 3,000 IU (75 kg * 40 IU/kg) to 5,700 IU (95 kg * 60 IU/kg) (see page 2035, paragraphs 3 and 4). Given the reasoning discussed above, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant application to combine the two references to treat AMR.
With regard to claim 42, Broom et al. teach the method of treating antibody-mediated rejection in an allograft transplantation recipient discussed above (see claims 1, 14) wherein C1-INH protein is administered at a dose of about 20,000 units given in divided doses over a duration of about 1 to 30 days, specifically 13 days (see claims 1, 10, 11, 14, 24, and 25). Craig et al. do teach the administration of the drug at a dose of 40-60 IU/kg, and they also teach that the patients receive iv-doses of C1-INH. Given the reasoning discussed above, it would have been obvious to one of ordinary skill prior to the effective filing date of the instant application to combine the references to teach the treatment of AMR according to the schedule recited in Craig et al. wherein the patient receives iv-doses according to the method of Broom et al. As such, one of ordinary skill in the art prior to the effective filing date of the instant application would have a motivation to use the method of Broom et al. as recited in claims 1, 11, 14, and 25 with iv-doses. Further, Craig et al. teach the method discussed above wherein the total amount of C1-INH administered subcutaneously ranges from 96,000 IU (75 kg * 40 IU/kg * 32 doses) to 182,400 IU (95 kg * 60 IU/kg * 32 doses) over 16 weeks with twice-weekly sc-doses (see page 2035, paragraphs 3 and 4). Given the reasoning discussed above, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant application to combine the two references to treat AMR.
With regard to claim 46, Broom et al. teach the method of treating antibody-mediated rejection in an allograft transplantation recipient discussed above (see claims 1, 14), but they do not explicitly teach that the method comprises subcutaneously administering C1-INH over at least 10 weeks wherein each week at least one sc-dose is administered. Craig et al. do, however, teach the method discussed above comprising subcutaneously administering C1-INH over 16 weeks wherein doses are administered twice weekly (see page 2035, paragraphs 3 and 4). Given the reasoning above, it would have been obvious to one of ordinary skill prior to the effective filing date of the instant application to combine the two references to treat AMR.
Claims 1, 22, and 23 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-27 of U.S. Patent No. 9895428 (provided on the IDS submitted 05/18/2023), hereinafter Broom et al. in view of Craig et al. (Craig, Timothy et al. "Treatment effect of switching from intravenous to subcutaneous C1-inhibitor for prevention of hereditary angioedema attacks: COMPACT subgroup findings." The journal of allergy and clinical immunology, vol. 7, 6 (2019): 2035-2038) and further in view of Metzner et al. (provided on the IDS submitted 05/18/2023, Document ID: US20190175683, published 06/13/2019).
Broom et al. claim a method for treating or preventing antibody-mediated rejection of a transplanted organ comprising administering a C1-INH protein (see claims 1 and 14). Specifically, Broom et al. claim a method of treating AMR of a kidney allograft in a patient in need thereof, the method comprising administration of a C1-INH protein at a dose of about 20,000 units given in divided doses over a duration of about 1 to 30 days, wherein the administration is initiated within 1 to 90 days of organ transplantation, treatment with plasmapheresis, treatment with IVIg, or diagnosis of AMR of the patient, wherein the method results in a therapeutic effect lasting for at least 3 months after cessation of therapy (see claim 14). Broom et al. do not, however, teach the administration of iv-doses of C1-INH followed by the administration of sc-doses of C1-INH over at least 10 weeks.
Craig et al. teach a method of treating HAE comprising the patient first receiving iv-doses followed by sc-doses (see page 2035, paragraphs 3 and 4). Craig et al. teach a method of treating hereditary angioedema (HAE) attacks comprising a subject receiving human C1-INH according to a schedule comprising the following steps: a) intravenously received one or more iv-doses of C1-INH, then b) subcutaneously receiving C1-INH over at least 10 weeks, wherein each week at least one sc-dose is administered (see page 2035, paragraphs 3 and 4). Specifically, they teach the subcutaneous use of C1- INH over 16 weeks (see page 2035, paragraphs 3 and 4). Craig et al. teach that patients previously using C1-INH(IV) at various doses as routine prophylaxis can experience a substantial and clinically meaningful reduction in HAE attack rate when switching to C1-INH(SC) (see page 2037, paragraph 2). Craig et al. do not teach a method of treating antibody-mediated rejection in a transplant recipient.
Although Broom et al. do not explicitly claim the schedule of administration recited above in Craig et al., there existed a clear motivation for the combination of the references in the art prior to the effective filing date of the instant application. Specifically, Metzner et al. teach the method described above and applied to claims 1, 2, and 28. Metzner et al. teach pharmaceutical formulations and uses of C1-INH for use in treating HAE and in preventing rejection of transplanted tissue in a kidney transplant recipient patient (see [0039], [0017]). Metzner et al. teach the use of subcutaneous or intravenous injections of C1-INH to treat the conditions, and they teach an efficient mode of operation for the treatment by standardizing its use in a kit (see [0014], [0161]). In other words, their method is pharmaceutically and therapeutically efficient because it allows for high concentrations of C1-INH and has an increased C1-INH stability (see [0013]). This provides a clear motivation for using or modifying injection-based C1-INH treatments of HAE, like that of Craig et al., for use in patients with AMR.
With regard to Broom et al. and Craig et al., Metzner et al. teach the use of intravenous and subcutaneous injections of C1-INH for treatment of the same patient population as Craig et al. and Broom et al., as Metzner et al. teach the treatment of patients with HAE and transplant patients with AMR after organ transplantation (see [0014], [0039]). Here, Metzner teaches the same method of treatment for the same groups of patients as compared to Craig et al. and Broom et al., and Metzner also show that their teachings provide benefits including increased stability of the C-INH (see Abstract). Given the fact that they use the same medication to treat the same patient populations and each demonstrate promising clinical or practical benefits, Metzner et al. provide a motivation to combine the references in the treatment C1-INH-related conditions. As such, it would have been obvious a person of ordinary skill in the art prior to the effective filing date of the instant application to combine the teachings of the references.
With regard to claim 1 of the instant application, Broom et al. claim a method of treating antibody-mediated rejection (AMR) of a kidney allograft in a patient in need thereof, the method comprising administration of a C1 esterase inhibitor (C1-INH) protein at a dose of about 20,000 units given in divided doses over a duration of about 1 to 30 days, wherein the administration is initiated within 1 to 90 days of organ transplantation, treatment with plasmapheresis, treatment with intravenous immunoglobulin (IVIg), or diagnosis of AMR of the patient, wherein the method results in a therapeutic effect lasting for at least 3 months after cessation of therapy (see claim 14). Though the scope of claim 1 of Broom et al. broadly encompasses the specific schedule of claim 1 of the instant application, Broom et al. do not distinctly claim said schedule. Craig et al. do, however, teach that patients receive iv-doses followed by sc-doses. Specifically, they teach a method of treating hereditary angioedema (HAE) attacks comprising a recipient receiving human C1-INH according to a schedule comprising the following steps: a) intravenously received one or more iv-doses of C1-INH, then b) subcutaneously receiving C1-INH over 16 weeks, wherein each week two sc-doses are administered (see page 2035, paragraph 4). Given the reasoning provided above, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant application to combine the references of Broom et al. and Craig et al. to treat AMR with a reasonable expectation of success, given the motivation provided by Metzner et al.
With regard to claim 22, Broom et al. claim the method discussed above (see claims 1, 14), but Broom et al. do not teach that each iv-dose comprises the same amount of C1-INH as each sc-dose. Metzner et al. teach the method discussed above wherein each iv-dose comprises the same amount of C1-INH as each sc-dose (see [0014], [0038]). Metzner et al. further teach that patients can self- administer the provided formulations either intravenously or subcutaneously (see [0151], [0152]), and that the provided formulations exhibit a high local tolerance both for subcutaneous and intravenous administration (see [0154]). As such, Metzner et al. provide a motivation for use of these formulations in both subcutaneous and intravenous injections because they provide both practical and clinical benefits. Given the reasoning above, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant application to combine the references.
With regard to claim 23, Broom et al. claim the method discussed above (see claims 1, 14), but they do not teach that the C1-INH has a concentration of about 200-800 IU/mL. Metzner et al. teach the method discussed above wherein the C1-INH is administered intravenously or subcutaneously at a concentration of about 400-2,000 IU/mL, preferably about 500 IU/mL (see [0079]). At this concentration, about 500 IU/mL, Metzner et al. observed long term stability for the pharmaceutical composition, providing a clear motivation to use said concentration, seeing as it provides practical benefits (see [0204]). Given this and the reasoning above, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant application to combine the references and use a concentration of C1-INH at 500 IU/mL in order to improve stability of the composition. Although Metzner et al. explicitly teach a motivation for using a concentration of about 500 IU/mL, they do not teach the entire range claimed in claim 23 of the instant application. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Geisler, 116 F.3d 1465, 1469-71, 43 USPQ2d 1362, 1365-66 (Fed. Cir. 1997) (Claim reciting thickness of a protective layer as falling within a range of "50 to 100 Angstroms" considered prima facie obvious in view of prior art reference teaching that "for suitable protection, the thickness of the protective layer should be not less than about 10 nm [i.e., 100 Angstroms]." The court stated that "by stating that 'suitable protection' is provided if the protective layer is 'about' 100 Angstroms thick, [the prior art reference] directly teaches the use of a thickness within [applicant's] claimed range."). Here, Metzner et al. state that increased long term stability is provided if the concentration is about 500 IU/mL (see [0204]), which, based on the caselaw provided above in Geisler, thereby teaches the use of the concentration in Applicant's claimed range of 200 IU/mL to 800 IU/mL.
Response to Arguments regarding NSDP rejections
The Applicants’ response filed on April 15, 2026 has been fully considered but is unpersuasive for reasons provided in the body of the rejections above. The applicants argue that there is no motivation to combine Bloom (patented claims) with Montgomery or with Craig, Fryar, and Viglietti. Specifically, the applicants argue that the Boom (patented) claims are distinct from the instant claims.
However, this argument is unpersuasive because in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). While Montgomery teaches high-dose intravenous regiment, Craig teaches a dosing regimen of C1-INH involving initial intravenous administration followed by subcutaneous dosing over a 16 week period for treating HAE. Further, in response to applicant's argument that there was no motivation to combine the references, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). Further, the applicants’ argument regarding the Montgomery reference does not show significant clinical results based on the Phase III clinical trial of NCT02547220, a prior art reference is available for all that it teaches. Montgomery et al. teach the method of treating antibody- mediated rejection in an allograft transplantation recipient discussed above comprising intravenous administration of an initial infusion of 5000 U of C1 INH followed by 2500 U of C1 INH every other day for 2 weeks (20,000 units over 13 days) (see page 3469, paragraph 7, Treatment and sample collection, and page 3474, paragraph 1). Montgomery et al. teach the method discussed above wherein 100 mg doses of IVIg/kg are used in addition to the administration of C1-INH (see page 3469, paragraph 7, Treatment and sample collection).
In addition, regarding the argument regarding no reasonable expectation of success and unexpected results, the arguments of counsel cannot take the place of evidence on the record. Further, the examples provided in the argument from the instant specification for producing such unexpected results are not commensurate with the scope of the present claims.
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.
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/CATHERINE S HIBBERT/Primary Examiner, Art Unit 1658
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