DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 01/30/2026 has been entered.
Status of the Application
Receipt is acknowledged of Applicants’ preliminary amendment, filed on 01/30/2026, in which claims 1 and 17 are amended, claims 9, 11, 13-16, and 23-26 are cancelled, and claims 27-36 are newly added. Claims 1-8, 10, 12, 17-22, and 27-36 are pending.
Claims 7-8, 10, and 12 are withdrawn from consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim in the office action of 01/31/2025.
Claims 1-6, 17-22, and 27-36 are examined on the merits herein.
Priority
The instant application is a DIV of 16/331,127 filed on 03/06/2019, which is a 371 of PCT/US17/50385, filed on 09/07/2017, which claims domestic benefit to 62/384,341 filed on 09/07/2016.
Warning Withdrawn
Applicant’s amendment and remarks, filed 01/30/2026, with respect that claim 26 is a substantial duplicate of claim 25 has been fully considered and is persuasive, as claims 25 and 26 are canceled.
Rejections Withdrawn
Applicant’s amendment and remarks, filed 01/30/2026, with respect that claims 1-6 are rejected under 35 U.S.C. 103 as being unpatentable over Bhaskar et al. (Carbohydrate Polymers, 2015) has been fully considered and is persuasive, as the scope of the claims have been amended to require a glycosaminoglycan comprising a 0.6-27% of NS2S disaccharide group, 0.4-11.8% of 0S disaccharide group, 0.4-14.4% of 6S disaccharide group, 0.0-1.9% of 2S disaccharide group and 0-3.2% of 2S6S disaccharide group. This rejection has been withdrawn.
The following are new grounds of rejection.
Claim Rejections - 35 USC § 103
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 1-6, 17-22, and 27-36 are rejected under 35 U.S.C. 103 as being unpatentable over Dordick et al. (WO 2012/116048 A1; IDS 01/20/2023) in view of Bhaskar et al. (Carbohydrate Polymers, 2015; IDS 1/20/2023).
Dordick discloses that production of a bioengineered heparin that is substantially identical to pharmaceutical heparin (page 2, lines 6-11). First, Dordick discloses a partial N-deacetylation and depolymerization of heparosan in NaOH (page 2, lines 21-23). This product may then be selectively N-sulfonated to obtain a ratio of N-acetylglucosamine and N-sulfoglucosamine equivalent to pharmaceutical heparin. The product of N-sulfonation is further processed as follows: (1) C5-epimerization/2-O-sulfonation with an equi-unit mixture of C5-epimerase and 2-O sulfotransferase; (2) 6-O-sulfonation with an equi-unit mixture of 6-O-sulfotransferase-1 and -3; and (3) 3-O-sulfonation with 3-O-sulfotransferase-1 in the presence of a PAPs regeneration system. Dordick teaches that this method produces bioengineered heparin which is substantially equivalent to pharmaceutical heparin with respect to N-acetylglucosamine and N-sulfoglucosamine levels and number average molecular weight (MN), weight average molecular weight (Mw) and polydispersity index (PDI). The bioengineered heparin has a clotting time substantially equivalent to pharmaceutical heparin (Page 4, lines 3-7).
Dordick states that all major disaccharide components present in pharmaceutical heparin can also be found in the bioengineered heparin except for ∆UA2S-GlcNAc6S and provides a comparison of the disaccharide compositions of bioengineered heparin as compared to commercial USP heparin in table 4.
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Dordick thus teaches a heparin having 11.8% 0S, 25.3% NS, 1.6% 6S, 1% 2S, 3.6% NS6S, 10.4% NS2S, 0% 2S6S, and 46.2% NS6S2S. To arrive at this product Dordick thus teaches a glycosaminoglycan that before step (3) 3-OST-1 modification does not comprise 3S disaccharide groups, and has 11.8% 0S, 25.3% NS, 1.6% 6S, 1% 2S, 3.6% NS6S, 10.4% NS2S, 0% 2S6S, and 46.2% NS6S2S. This glycosaminoglycan has a combined amount of the 0S disaccharide group, the 6S disaccharide group, the 2S disaccharide group and the 2S6S disaccharide group of 14.4%.
The teachings of Dordick differ from that of the instantly claimed invention in that Dordick does not teach a glycosaminoglycan having 1-22% of NS and 6-40% of NS6S (instant claims 1 and 17), 6-32% of NS6S (instant claims 2-4 and 18-20), or the weight properties of instant claims 6 and 22.
Bhaskar discloses a combinatorial study of multi-enzyme, one-pot, in vitro biocatalytic synthesis of heparin and its derivatives. This study helps to provide safer bioengineered heparin using bacterial capsular polysaccharide heparosan and recombinant enzymes derived from the heparin/heparan sulfate biosynthetic pathway (abstract). Bhaskar teaches that Heparin, the first biopolymeric drug, possesses a wide range of structural heterogeneity owing to its biosynthesis (page 399, paragraph 1).
In order to reduce product complexity and thereby simplify analysis (3-O-sulfo group containing sequences are resistant to heparin lyases and thus do not afford disaccharide products), Bhaskar includes an initial combinatorial synthesis in which the enzyme 3-OST-1 was not included (page 400, paragraph 4). Thus the products of the initial combinatorial syntheses of Bhaskar have not had 3-O-sulfo groups installed and are derivatives of heparin. Furthermore, the substrate for the initial combinatorial chemoenzymatic heparin synthesis experiments were carried out using NSH as substrate (page 400, paragraph 4), which does not have 3-O-sulfo groups.
Bhaskar teaches that post the 2008 contamination crisis, USP has actively engaged in inclusion of enhanced standards of purity and stricter quality control toward minimization of variation within commercial heparin products. For increased clinical safety, the USP has imposed several restrictions on heparin’s molecular weight properties as they are known to impact its biological activity (page 405, paragraph 1). Bhaskar further teaches that the USP heparin has the following characteristics (page 405, paragraphs 1-2).
1. Proportion of heparin chains with molecular weight over 24,000 is not more than 20%.
2. Mw is between 15,000 and 19,000.
3. The ratio of heparin chains with molecular weight between 8000 and 16,000 Da to heparin chains with molecular weight between 16,000 and 24,000 is not less than 1.0.
Bhaskar teaches that the resulting molecular weight of bioengineered products is directly related to the NSH substrate molecular weight. Therefore, control over the NSH molecular weight during the chemical N-deacetylation/N-sulfonation and titanium dioxide depolymerization can effectively generate one-pot heparin products within the new regulatory requirements (page 405, paragraph 3).
Regarding the optimization of NS disaccharides, Bhaskar teaches that decreasing the amount of NS content is reflective of increased conversion of available substrate sites into other disaccharide types, including, among others, NS6S (page 402, paragraph 2). For example, reactions 3, 5, and 7 in Table 1 (page 403) show a decreased percentage of NS as a result of increasing the amount of C5-epi and/or 2-OST enzyme in the reaction. Similarly, Reactions 8, 10, and 12 in Table 2 (page 403) show decreased NS percentage as a result of increasing 6-OST-1 and/or 6-OST-3 treatment.
Regarding the optimization of NS6S disaccharides, Bhaskar teaches that enhanced 6-O-sulfation rapidly catalyzes the formation NS6S (page 402, paragraph 5). Reactions 8, 10, and 12 in Table 2 (page 403) show increased NS6S percentage as a result of increasing the amount of 6-OST-1 and/or 6-OST-3 enzyme in the reaction.
One of ordinary skill in the art would have been motivated to improve the disaccharide percentages of the glycosaminoglycan of Dordick to better align with USP heparin specifications by optimizing the N-sulfonation modifying reactions in light of the teachings of Bhaskar to arrive at the instantly claimed invention because Dordick discloses a bioengineered heparin that is substantially identical to pharmaceutical heparin and Bhaskar provides a combinatorial study of multi-enzyme, one-pot, in vitro biocatalytic synthesis of heparin. It would have been prima facie obvious for one of ordinary skill in the art to modify the NS6S content of the glycosaminoglycan of Dordick to match to the USP limitation of 5.4-10.8% taught by Dordick by optimizing the amount of 6-OST-1 and/or 6-OST-3 enzymes included in the reaction conditions as taught by Bhaskar. Similarly, it would have been prima facie obvious for one of ordinary skill in the art to modify the NS content of the glycosaminoglycan of Dordick to match the USP limitation of 0.8-5.4% taught by Dordick by optimizing the amount of epimerization and sulfotransferase enzymes included in the reaction conditions as taught by Bhaskar. One of ordinary skill in the art would have a reasonable expectation of success because both Bhaskar and Dordick teach intermediates in the synthesis of a bioengineered heparin using the same enzymes: C5-epi, 2-OST, 6-OST-1, and 6-OST-3.
Regarding the ranges of the percentage of NS6S and NS disaccharide group, Dordick discloses a USP heparin comprising NS6S disaccharide at 5.4-10.8% and NS disaccharide at 0.8-5.4% (Table 4, reproduced in part above for convenience) and teaches and suggests a glycosaminoglycan having these percentages. Thus the ranges of claims NS and NS6S in instant claims 1-4 and 17-20 overlap ranges disclosed by the prior art. MPEP 2144.05(I) states that “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists.” Thus, the limitations of claims 1-4 and 17-20 are rendered prima facia obvious by the disclosure of the USP heparin.
Regarding claims 6 and 22, it would have been prima facie obvious before the effective filing date of the claimed invention to synthesize the heparin derivatives of Dordick with the molecular weight characteristics of USP heparin as described by Bhaskar to arrive at the instantly claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to synthesize heparin derivatives with these molecular weight characteristics using the synthesis of Dordick because Dordick teaches a synthesis of compounds with characteristics of heparin, and Bhaskar teaches that molecular weight characteristics contribute to the biological properties of heparin. One of ordinary skill in the art would have a reasonable expectation of success because Bhaskar teaches that the resulting molecular weight of bioengineered derivatives is directly related to the NSH substrate molecular weight and so control over the NSH molecular weight during the chemical N-deacteylation/N-sulfonation and titanium dioxide depolymerization can effectively generate one-pot heparin derivatives within the new regulatory requirements.
Response to Arguments
Applicant's arguments filed 01/30/2026 have been fully considered but they are not persuasive.
Insofar as Applicant’s arguments are applicable to the current rejection, Applicant argues that Bhaskar does not teach a glycosaminoglycan having 0.4-11.4% of 6S disaccharide group (remarks, paragraph bridging pages 6-7), and that Bhaskar’s process could not be modified to achieve that disaccharide percentage (remarks, paragraph bridging pages 7-8). This is not persuasive.
The current rejection depends on the teachings of Dordick, which discloses a glycosaminoglycan having 1.6% 6S disaccharide, and so the rejected claims are prima facie obvious over the combined teachings of Dordick and Bhaskar.
Allowable Subject Matter
Claims 5, 21, and 31-36 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. The following is a statement of reasons for the indication of allowable subject matter.
Claims 5, 21, and 31-36 are drawn to a glycosaminoglycan having particular percentages of disaccharides. The closest prior art is Dordick, which teaches the synthesis of glycosaminoglycans for the production of synthetic heparin and provides teachings on the disaccharide content of the glycosaminoglycans.
However, regarding claims 5 and 21, Dordick does not teach or suggest a glycosaminoglycan having 12-27% of NS2S disaccharide group. Rather, Dordick teaches an intermediate glycosaminoglycan for the production of a heparin having 10.4% of NS2S disaccharide group, and teaches that USP heparin has 3.7-11.6% of NS2S disaccharide group. Neither Dordick nor the prior art provides motivation to select an NS2S content of 12-27%. Thus it would not be prima facie obvious for one of ordinary skill in the art to modify the glycosaminoglycan of Dordick to match the claimed disaccharide percentages.
Regarding instant claims 31-36, Dordick does not teach or suggest a glycosaminoglycan having 2S6S groups. Neither Dordick nor the prior art teaches a method of optimizing the amount of 2S6S disaccharides in the enzymatic synthesis of bioengineered heparin. Thus one of ordinary skill in the art would not have a reasonable expectation of success in synthesizing the claimed glycosaminoglycan of instant claims 31-36.
Conclusion
No claims are allowed.
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/S.G.H./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693