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
As discussed in the telephonic interview held on 9/12/2025, Examiner verifies that a restriction requirement was mailed on 11/8/2024. The species election requirement was withdrawn based on the election of Group I: claims 1-8, as set forth in the non-final office action mailed on 7/29/2025.
Claims 1-9 and 41-60 are pending and under examination herein.
Priority
This application is a 371 of PCT/US2020/049156 filed on 9/3/2020, which claims benefit of 62/983,862 filed 3/2/2020 and 62/895,230 filed 9/3/2019. The effective filing date of the instant application is September 3, 2019.
Information Disclosure Statement
The information disclosure statements filed on January 28, 2026 complies with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. All references have been considered.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Maintained rejection: Claims 1-9 and 41-60 remain rejected under 35 U.S.C. 103 as being unpatentable over Kraus et al. (US 2018/0318404 A1, published November 8, 2018; previously cited) in view of Stabler et al. (“Metabolic Profiling of Total Homocysteine and Related Compounds in Hyperhomocysteinemia: Utility and Limitations in Diagnosing the Cause of Puzzling Thrombophilia in a Family”, JIMD Reports, 2013, Volume 11, pp.149-163; previously cited). The rejection of claims 58 and 60 is further evidenced by Bonadio ("Macaca fascicularis" (On-line), Animal Diversity Web, 2000; Accessed July 22, 2025 at https://animaldiversity.org/accounts/Macaca_fascicularis/; previously cited)
Regarding claim 1, Kraus teaches a method of treating homocystinuria in a subject, said method comprising administering to a subject a composition comprising an isolated human truncated cystathionine B Synthase (htCBS) mutant polypeptide, wherein the isolated htCBS polypeptide mutant has been PEGylated (description p.49, claim 1). Kraus teaches that the levels of tHcy (FIG. 6A), cystathionine (FIG. 6B), and cysteine (FIG. 6C) in HO mice injected with 7.5 mg/kg of PEGC15S or PBS (n=5) 1, 4 and 24 hours post injection were measured (description p.19, [0183]). Kraus teaches a truncated recombinant human CBS where the C-terminal regulatory region has been removed, and mutated where cysteine at amino acid position 15 has been changed to serine (description p.6, [0065]), SEQ ID NO:13, which has 100% homology to instant SEQ ID NO:1.
Kraus does not teach wherein the subject is a non-genetically defined patient having elevated tHcy levels or a non-genetically defined patient having CBS deficiency.
However, Stabler teaches metabolic profiling of total homocysteine and related compounds in hyperhomocysteinemia (title). Stabler teaches patients presenting with lower cystathionine, elevated methionine, and decreased cysteine, a pattern suggestive of CBS deficiency (abstract). Stabler teaches that there are likely other undiagnosed, highly B6-responsive adult patients with CBS deficiency, and that additional testing of cystathionine, total cysteine, methionine, and S-adenosylmethionine will be helpful in diagnosing them correctly and distinguishing CBS deficiency from remethylation defects (abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to select a patient having elevated homocysteine levels as taught by Stabler as the subject whose plasma concentration of homocysteine, cystathionine and cysteine are measured in the method of Kraus. One of ordinary skill in the art would have been motivated to select a patient with elevated homocysteine levels for measuring plasma concentrations of homocysteine, cystathionine and cysteine because Stabler identifies that testing for these compounds would be helpful in distinguishing CBS deficiency from remethylation defects. One of ordinary skill in the art would have found it beneficial to select patients presenting elevated homocysteine levels to help diagnose whether a patient had CBS deficiency or had a remethylation defect.
Regarding claim 2, Kraus teaches CBS deficiency is characterized by highly elevated blood levels of homocysteine (Hcy), methionine and S-adenosyl-homocysteine accompanied by low levels of cysteine and cystathionine (description p.6, [0059]). Kraus further teaches that in classical homocystinuria, the plasma methionine level usually increases above the normal range of 30 micromoles/L and the concentrations should be monitored as potentially toxic levels may be reached (description p.6, [0061]). Kraus teaches that after injection with a PEGylated form of htCBS, blood was collected at various time-points from the submandibular vein of conscious study animals, and plasma was collected from blood samples after centrifugation (description p.15, [0159]).
Regarding claims 3-6 and 47-51, Kraus teaches 20 NHS PEG-htCBS C15S in humans at SC doses of 0.33, 0.66, and 1 mg/kg administered once per week and twice per week (description p.38, [0354]), which fall within the claimed dose ranges.
Regarding claims 3-7, Kraus teaches wherein the isolated htCBS mutant polypeptide is administered in a dose between about 0.01 and 10 mg/kg (description p.49, claim 1), which overlaps with the claimed dose ranges.
Regarding claims 8-9 and 41-46, Kraus teaches PEGylated htCBS or PEGylated htCBS mutant may be used to reduce tHcy levels in a subject with CBSDH (description p.8, [0091]). Kraus teaches monitoring serum homocysteine levels and cystathionine levels in HO mice (description p.18, [0178]). Kraus teaches blood samples were collected from HO mice at 24 hours and 72 hours post injection, and plasma tHcy was reduced (description p.18, [0180]; FIG. 4A; FIG. 4C).
Regarding claims 52-54, 57 and 59, Kraus teaches wherein the dose is an amount selected from the group consisting of: about 0.01, about 0.1, about 0.5, about 1, and about 5 mg/kg (description p.49, claim 17).
Regarding claims 55 and 56, Kraus teaches the administration of the PEGylated htCBS mutant may follow a dosing schedule of a series of doses that has a gap between the first series and the second series of doses, where the gap between doses may be 3 days or 4 days; the number of doses in a series may be 2, 3, 4, 5 or 6 (description p.10, [0106]), which encompasses the claimed range of a first series of a first dose twice a week for two weeks and a second series of a second dose twice a week for at least 6 weeks.
Regarding claims 58 and 60, Kraus teaches the dose of PEGylated htCBS mutant administered to a subject is selected from the range of about 2 mg/kg to about 24 mg/kg (description p.10, [0110]). Kraus teaches the administration of 20 NHS PEG-htCBS C15S to wild-type cynomolgus monkeys (Macaca fascicularis) (description [0332]). As evidenced by Bonadio, the average weight of a monkey is about 7 kg. Thus, Kraus teaches administering a dose comprising 100 mg or 150 mg of 20NHS PEG-CBS [claim 58] or a dose comprising 200 mg, 250 mg or 300 mg 20NHS PEG-CBS [claim 60].
The amount of a specific ingredient in a composition is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient to add in order to best achieve the desired results.
It would have been obvious to one of ordinary skill in the art at the time of the invention to engage in routine experimentation to determine optimal or workable ranges that produce expected results. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. In re Aller, 220 F. 2d 454, 105 USPQ 233 (CCPA 1955). NOTE: MPEP §2144.05.
Response to Arguments
Applicant argues that the office admits the Kraus reference does not disclose wherein the subject is a non-genetically defined patient having elevated tHcy levels or a non-genetically defined patient having CBS deficiency, and the office points to the teachings of Stabler to account for this deficiency (See Remarks dated 1/28/2026, p.9, 1st paragraph). Applicant argues that Stabler does not account for the “non-genetically defined patient” of claim 1, because the patients at issue in this reference were a subset of patients who are compound heterozygotes for mutations in the gene that encodes CBS, and cites p.157, 2nd column last paragraph of Stabler (p.9 last paragraph to top of p.10). Applicant argues that claim 1 has been amended such that the “metabolic indicator” does not include the combination of homocysteine, cystathionine and cysteine, so the claimed methods are distinguished from the teachings of Kraus in view of Stabler (See Remarks dated 1/28/2026, p.10).
Applicant's arguments filed January 28, 2026 have been fully considered but they are not persuasive. As discussed in the rejection above, Kraus teaches a method of treating cystathionine β-synthase (CBS) deficiency in a subject comprising: steps of determining a level of a metabolic indicator of disease severity in a subject; administering to the subject a therapeutically effective amount of a pharmaceutical formulation comprising a drug substance comprising an isolated cystathionine β-synthase (CBS) protein comprising SEQ ID NO:1; a PEG molecule covalently bound to the CBS protein, and a pharmaceutically acceptable diluent (PBS); wherein the metabolic indicator is at least one selected from the group consisting of total homocysteine (tHcy) and methionine. Stabler is relied upon to teach metabolic profiling of total homocysteine and related compounds, and identifies patients with lower cystathionine, elevated methionine and decreased cysteine is a pattern suggestive of CBS deficiency. Stabler further teaches that additional testing of cystathionine, total cysteine, methionine, and S-adenosylmethionine will be helpful in diagnosing these patients correctly and distinguishing CBS deficiency from re-methylation defects.
Although Applicant has amended claim 1 to limit the metabolic indicator of disease severity to a specific group of alternatives, the method comprises the steps and does not exclude additional steps of determining levels of additional metabolic indicators other than total homocysteine and methionine, which are taught by both Kraus and Stabler. Although Applicant identifies that Stabler’s patient population included genetically-defined patients, Stabler was relied upon to teach that metabolic indicators could be measured in any patient population (abstract), which would include non-genetically defined patients presenting with elevated methionine, lower cystathionine and decreased cysteine.
Conclusion
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.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DEEPA MISHRA whose telephone number is (571) 272-6464. The examiner can normally be reached Monday - Friday 9:30am - 3:30pm EST.
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/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/DEEPA MISHRA/Examiner, Art Unit 1657