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 .
Status of the Application
Receipt is acknowledged of Applicants’ amendment and remarks, filed on 09/24/2025, in which claim 1 is amended, claims 7-9 and 16 are canceled, and claims 24-25 are new. Claims 17-23 are withdrawn from consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim in the office action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 12/12/2024. Claims 1-6, 10-15, and 24-25 are examined on the merits herein.
Priority
The instant application is a continuation of 17/206,643 filed on 03/19/2021, which claims domestic benefit to 62/991,804 filed on 03/19/2020.
Rejections Withdrawn
Applicant’s amendment and remarks, filed 09/24/2025, with respect that claims 7-8 are rejected under 35 U.S.C. 103 as being unpatentable over Jozefiak in view of Place has been fully considered and is persuasive, as claims 7-8 are canceled.
This rejection has been withdrawn.
The following are modified grounds of rejection necessitated by Applicant’s amendment, in which claims 24-25 are added and claim 1 is amended to recite wherein the linking agent is divinyl sulfone and the pendant linking group is vinyl, which are the limitations of both claims 7 and 8.
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, 10-15, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Jozefiak et al. (WO 2018/053276 A1; IDS 04/09/2024) in view of Place et al. (Biomacromolecules, 2014; PTO-892 03/24/2025).
Jozefiak discloses polymer conjugates mimicking the functions of natural proteoglycan mimics (abstract). Jozefiak discloses a GAG conjugate in which a linear GAG backbone bears additional sulfated GAG chains connected by linking groups to form a branched polymer conjugate (Figure 3), which is soluble in aqueous solution (claim 1). Jozefiak teaches strategies to generate a proteoglycan mimic (page 11, lines 21-22) containing modifiers to provide additional benefits (page 15, lines 7-8). A preferred example of a modifier is a glycan ligand for galectins, for example a β-galactose residue (page 17, lines 7-10).
Jozefiak teaches that the backbone of the GAG conjugate is substantially linear (Figures 3-4). Jozefiak teaches that the resulting polymer is 15,000 Da - 1,000,000 Da (claim 19). Jozefiak teaches that the chondroitin sulfate has a MW of 14,000 Da (figure 5, and page 2, lines 12-13). Jozefiak teaches that the backbone GAG has 1.823 mmol equiv. hydroxyl groups and the linker is provided at 2.15 mmol (page 48, lines 7-10), which is a ratio of 1.18. Jozefiak teaches that the core polymer is a sulfated GAG identical to that added in the branch forming step (claim 25). Jozefiak teaches that the linking agent is divinyl sulfone (page 48, line 9), which installs a reactive vinyl group. Jozefiak teaches that the portion of sulfated GAG added in the backbone functionalizing vs GAG crosslinking step is 0.306g to 0.909g (page 48, lines 5-15), which is about 33/66. Jozefiak teaches that the modifier is lactosylamine (page 48, line 15), which is an epitope and therefore a targeting moiety. Jozefiak teaches that the modifier would comprise a hydrophobic moiety (page 5, line 28).
In example 12, Jozefiak discloses a conjugate in which the GAG chondroitin sulfate is reacted with DVS (linking agent) as step 1. Then the product of step 1 is reacted with more GAG and lactosylamine, which is a modifier (page 48, lines 4-21) and is a modified β-galactose residue. Jozefiak states the example demonstrates preparation of high molecular weight branched sulfated GAGs in the presence of a modifier "capable of reacting with the DVS-modified intermediate prepared in the first stage" (page 49, lines 19-21). This indicates that the conjugate has a backbone that is modified by a linker and that both GAG and modifiers are bound to that backbone through the linkers. Thus Jozefiak discloses a GAG conjugate encompassed by the recited structure as the instant claim 1.
The teachings of Jozefiak differ from that of the instantly claimed invention in that Jozefiak does not expressly teach that the pendant reactive groups are present in the soluble polymer formed in step ii) on between 2% and 30% of disaccharide repeat units, as determined by proton NMR.
Place teaches a method of synthesizing bottle-brush PG mimics with tunable density of the GAG side chains. The density of GAG side chains can be tuned to mimic the broad range of GAG substitution found in natural PGs by controlling the stoichiometry of the side chain added (page 3773, paragraph 2). Tuning the density of the side chains is desirable because it influences the biochemical properties of PG mimics; for example, a less dense PG mimic provided superior binding and delivery of fibroblast growth factor to cultured cells (page 3779, paragraph 4). These PG mimics comprise an activated core with linker groups (scheme 2) to which different stoichiometric ratios of polysaccharide branches are added (page 3775, paragraph 1). For the highest density PG mimics there is one polymer branch for every linker group, whereas a 1:30 PG mimics have only 1/30 of the stoichiometric amount of side chains added in comparison to the linker groups on the core (page 3775, paragraph 1).
Place teaches that by altering the stoichiometry of side chain added to the reaction mixture, the density of the PG mimic can be controlled. This includes the formation of PG mimics where not every liker is connected to a side chain, which results in linker moieties available for reaction with modifiers.
It would have been prima facie obvious before the effective filing date of the claimed invention to optimize the density of the GAG side chains in Jozefiak, thereby altering the percentage of pendant groups that bound to the lactosylamine modifier, according to the teachings of Place to arrive at the instantly claimed invention. One of ordinary skill in the art would have been motivated to optimize the side chain density of the compositions of Jozefiak because Place teaches that the density of GAG side chains influences the biochemical properties of PG mimics. One of ordinary skill in the art would have a reasonable expectation of success because both references teach the formation of bottle-brush polymer conjugates with GAG side-chains for use as PG mimics.
Instant claim 25 recites a GAG produced by the method of claim 1 wherein the modifier is in stoichiometric excess over the remaining pendant linking groups. The structural limitation required by this claim is interpreted in light of the instant specification – which states that a nucleophilic quencher compound is added in excess to fully react with all remaining vinyl-sulfone groups (specification, page 50, lines 24-25) – as indicating that the GAG does not contain free vinyl sulfone groups. In example 12, Jozefiak discloses a conjugate in which the GAG chondroitin sulfate is reacted with 2.15 mmol divinylsulfone, and then reacted with more GAG (7.25 mmol equiv. hydroxyl groups) and lactosylamine (0.107 mmol) (page 48, lines 4-21). Thus Jozefiak discloses a reaction in which sufficient GAG and modifier are added (greater than 2.15 mmol) to the vinyl substituted backbone GAG to fully react with all vinyl groups.
Claim 24 is rejected under 35 U.S.C. 103 as being unpatentable over Jozefiak et al. (WO 2018/053276 A1; IDS 04/09/2024) in view of Place et al. (Biomacromolecules, 2014; PTO-892 03/24/2025), as applied to claim 1, further in view of Neves et al. (Molecules, 2020; PTO-892).
The combined teachings of Jozefiak and Place teach the GAG of claim 1, as discussed in detail above. Jozefiak further teaches that modifiers can be small molecules (page 5, line 21), and be pharmacokinetics modifiers including, among others, hydrophobic groups (page 5, lines 26-29).
The combined teachings of Jozefiak and Place differ from that of the instantly claimed invention in that they do not expressly teach that the modifier is n-hexylamine.
Neves reviews the state of the art in the design of glycosaminoglycan-inspired biomaterials (abstract). Neves teaches that, in producing GAG-based biomaterials, most strategies resort to chemical modifications to add specific moieties to GAG. Such functionalizations allow the incorporation of new features to modulate properties such as biological performance (page 4, paragraph 3). Neves further teaches that GAG derivatives can be produced by including hydrophobic groups to modulate their hydrophilic nature, providing a GAG amphiphilic character that can be suitable for particular applications, such as the delivery of hydrophobic compounds. Reported amphiphilic derivatives comprise the incorporation of, among others, hexylamine (page 8, paragraph 3).
It would have been prima facie obvious to combine the teachings of Jozefiak, Place, and Neves before the effective filing date of the claimed invention by using the n-hexylamine of Neves as the hydrophobic modifier in the GAG biomaterial suggested by n-hexylamine to arrive at the instantly claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to modify the modifier of Jozefiak because it is obvious to substitute the known hexylamine GAG modifier of Neves as the GAG modifier in the GAG biomaterial of Jozefiak to obtain the predictable result of a GAG bearing amphiphilic character. One of ordinary skill in the art would have a reasonable expectation of success because Jozefiak teaches that the modifiers may be small molecules and may be hydrophobic charged groups, and Neves teaches that n-hexylamine is a GAG modifier suitable for providing a GAG with amphiphilic character.
Response to Arguments
Applicant's arguments filed 09/24/2025 have been fully considered but they are not persuasive.
Insofar as Applicant’s arguments are applicable to the current rejections, Applicant argues that because Jozefiak is silent on the 3-stage process as required in the present invention, it is impossible to produce a product as claimed using the method disclosed in Jozefiak (paragraph bridging page 9-10). Similarly, Applicant argues that Jozefiak and Place, neither alone nor in combination, teach a GAG conjugate of Stage 2 retaining pendant vinyl groups (page 9, paragraph 3). This is not persuasive.
Applicant’s arguments are directed to a method of producing a GAG. However, the instant claims are directed to a product produced by a method. MPEP 2113(I) states "[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." Furthermore, MPEP 2113(II) states that “once the examiner provides a rationale tending to show that the claimed product appears to be the same or similar to that of the prior art, although produced by a different process, the burden shifts to applicant to come forward with evidence establishing a nonobvious difference between the claimed product and the prior art product.”
Regarding the structural differences between the Applicant’s claimed product and that suggested by the combination of Jozefiak and Place, Applicant argues that the highest weight-average molecular weight reported in Jozefiak was 430,000 Da, as compared to instant Example 10, which produced a product of 2,470,000 Da (paragraph bridging page 7-8). This is not persuasive.
Applicant’s base claim is not limited to the weight-average molecular weight. Dependent claim 3 limits a product with a molecular weight of 100,000-5,000,000 Da. As discussed in the above grounds of rejection, Jozefiak teaches polymers with a molecular weight of 15,000 Da - 1,000,000 Da, and Place provides motivation for optimizing the size chain density, which would provide a corresponding alteration in the molecular weight.
Because Applicant’s arguments are not persuasive, the instant claims are rejected for the reasons of record with modifications made to account for the claim amendments filed 09/24/2025.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 extension fee 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 date of this final action.
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/S.G.H./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693