DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after 16 March 2013, is being examined under the first inventor to file provisions of the AIA .
Response to Amendments
Status of Claims
The amendment, filed on 26 May 2026, is acknowledged.
Claims 1-3 and 6 been amended.
Claims 1-3, 5-6, and 8-15 are pending and under consideration in the instant Office Action.
Objections Withdrawn
Objections to Specification
Applicant’s amendment to the title, submitted on 26 May 2026, has overcome the objection to the Specification set forth in the Office Action mailed on 27 January 2026. Accordingly, the relevant objection is withdrawn.
Rejections Withdrawn
Rejections pursuant to 35 U.S.C. § 103
The rejections of claims 1-3, 5-6, and 8-15 are under 35 U.S.C. § 103 are withdrawn in view of Applicant’s amendments to claims 1 and 6 and in favor of the new grounds of rejection below.
New Grounds of Rejection
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.
Claims 1-3, 5-6, and 8-12 are rejected under 35 U.S.C. 103 as being unpatentable over Aoi et al. (Macromol. Chem. Phys. 1994, 195 (12), 3747., provided by Applicant in IDS filed on 11 July 2025, hereafter referred to as Aoi) in view of Tomoki et al. (J. Mat. Chem. B 2019, 7, 6362., provided by Applicant in IDS filed on 10 March 2023, hereafter referred to as Tomoki), Schlaad et al. (Macromol. Rapid Commun. 2010, 31 (6), 507., hereafter referred to as Schlaad), and Kharkar et al. (Chem. Soc. Rev. 2013, 42, 7335., hereafter referred to as Kharkar).
Aoi teaches synthetic methods of producing chitin derivatives having poly(2-alkyl-2-oxazoline) side chains (Abstract). In the field of biomedical material design, Aoi teaches that “considerable attention has been directed toward synthetic polymers bearing informational carbohydrates” due to the role they play in biological events (pg. 3836, para. 1). Examples include polystyrene with an N-actylchito oligosaccharide on each repeating unit and a poly(2-methyl-2-oxazoline) macromonomer with N-acetyl-D-glucosamine at the w-end, as well as its graft-type polymer which was synthesized via living polymerization (pg. 3836, para. 1). To further investigate the functional material properties of sugar-containing polymers copolymerized with poly(2-alkyl-2-oxazoline), Aoi developed a synthetic method of producing artificial glycoconjugates with monodisperse side chains (pg. 3836, para. 3 and Scheme 1).
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Scheme 1, reproduced from Aoi above, demonstrates living cationic ring opening polymerization of 2-methyl- and 2-ethyl-2-oxazoline in acetonitrile (1a and 1b, respectively, in Scheme 1 above), initiated by methyl triflate, and terminated by reaction with partially deacetylated chitin (3 in Scheme 1 above) (pg. 3836 final para - pg. 3837, para. 1). The conjugation of poly(2-alkyl-2-oxazoline) oligomers to the modified chitin molecule occurs via reaction with an amino functional group on one or more D-glucosamine units (pg. 3837, final para.). The degree of substitution, represented as r/p in Table 1, ranges from 14-97% and is taught to be dependent on the concentration ratio of poly(2-alkyl-2-oxazoline) to D-glucosamine units in the modified chitin polysaccharide (pg. 3839, para. 1).
Aoi further teaches that solution temperature impacts molecular motion of the polymer, which is interpreted as a thermoresponsive polymer (pg. 3842, para. 2). Aoi reports that similar behavior has been observed in other carbohydrate-containing polymers, such as polystyrene derivatized with polysaccharides (pg. 3842, para. 2). In conclusion, Aoi teaches that this mechanism of grafting poly(2-alkyl-2-oxazoline) side chains onto biomacromolecules, such as deacetylated chitin, can improve solubility and warrants further investigation with other blends of graft copolymers and commodity polymers (pg. 3842, para. 3).
Aoi does not teach the molecular weight of their thermoresponsive polymer to be 5-100 kDa, the biomacromolecule to be hyaluronic acid, an aqueous solution containing the polymer at a concentration of 5-40% w/v, the storage modulus of the hydrogel, the gelation temperature to be 4-45 °C, nor use of the hydrogel to encapsulate a biologically active agent. These deficiencies are offset by the teachings of Tomoki, Schlaad, and Kharkar.
Tomoki teaches a method for the “preparation of self-healing and injectable hydrogels based on the crystallization-driven self-assembly of carbohydrate-conjugated poly(2-isoprolpyloxazoline)s” (Abstract). The use of poly(2-isopropyloxazoline) polymers (PiPrOxs) is taught to be advantageous because of their high water solubility and ability to self-assemble at temperatures above their lower critical solution temperature (LCST) of ~40 °C (pg. 6362, right column, final para.). Tomoki synthesized carbohydrate-conjugated PiPrOxs via cationic ring-opening polymerization of 2-isopropyl-2-oxazoline (iPrOx) with peracetylated carbohydrate bromides, said carbohydrates being glucose, maltotriose, or maltopentaose (pg. 6365, Results and discussion, para. 1). The carbohydrate-conjugated PiPrOxs polymers displayed thermoresponsive behavior in water and a LCST of ~39 °C (page 6365, Results and discussion, para. 2). Tomoki teaches that the polymers self-assemble into fibers in aqueous solution, which subsequently form hydrogels following incubation at 70 °C, and that “the gelation temperature coincides with the LCST” (pg. 6366, right column, para. 1 - pg. 6367, left column, para. 1). The hydrogel formation of the thermosensitive polymer-biomacromolecule conjugate is taught to be performed in an aqueous solution at a polymer concentration of 3% weight in 1 mL total solution (Tomoki, pg. 6364, Preparation of polymer solutions and The stability of the hydrogels in a physiological environment).
Tomoki teaches the molecular weight of their PiPrOx-glycopolymer to be 1.4 x 104 g/mol, which is equivalent to 14 kDa (pg. 6363, Experimental, Synthesis, Synthesis of glycopolymers). The carbohydrates in Scheme 1 are glucose (MW ~180 Da), maltotriose (three glucose molecules, MW ~504 Da), or maltopentaose (five glucose molecules, MW ~900 Da), resulting in a polyoxazoline polymer with a MW that is ~13-14 kDa. Further, Tomoki teaches the storage modulus (G’) of their thermosensitive polymer-biomacromolecule conjugate hydrogels to be ~1 x 104 Pa, as measured by a rheometer, at 25 °C (Figures 5 and S17). These values were not obtained at the gelation temperature nor above the gelation temperature or 37 °C as recited in instant claims 11-12. However, the hydrogels taught by Tomoki were stable at biological temperatures under the dorsal skin of mice for two weeks following transplantation and Figure 9 of the instant application demonstrates that G’ increases above the gelation temperature for thermosensitive polymer-biomacromolecule conjugate hydrogels (pg. 6368, right column, para. 1). Therefore, the G’ values obtained by Tomoki at 25°C would necessarily be greater than 100 Pa at 37 °C and at or above the gelation temperature. Tomoki concludes by teaching that their hydrogels may be used to encapsulate drugs and subsequently release those drugs into an area in which the hydrogels have been transplanted (pg. 6368, Conclusions).
Guidelines on the obviousness of similar and overlapping ranges, amounts, and proportions are provided in MPEP § 2144.05. With respect to claimed ranges which “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). In the above decisions, “the prior art taught carbon monoxide concentrations of ‘about 1-5%’ while the claim was limited to ‘more than 5%.’ The court held that ‘about 1-5%’ allowed for concentrations slightly above 5% thus the ranges overlapped.” With respect to ranges or amounts that do not overlap but are merely close, courts held that a prima facie case of obviousness also exists. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985). These guidelines apply to the polymer concentration of 3% taught by Tomoki, the storage modulus, the molecular weight, and the degree of substitution. In each instance, the prior art either teaches a value that falls within the recited range or is sufficiently close to render the recited range prima facie obvious.
Schlaad teaches poly(2-oxazoline)s as “smart” bioinspired polymers due to having materials and solution properties that can be adjusted via the nature of side chains, “opening the way to stimulus-responsive materials and complex colloidal structures in aqueous environments” (Abstract). Poly(2-oxazoline)s are taught to have structural relation to polypeptides, but usually lack chiral centers in the primary chain and therefore cannot form distinct secondary structures via hydrogen bonding like natural polypeptides (pg. 511, right column, para. 1). However, these features can be introduced via modifications to side chains or the terminating ends – for example, polyoxazolines with short alkyl side chains (such as poly(2-isopropyl-2-oxazoline)) impart water solubility to the polymers and can exhibit lower critical solution temperatures (LCST) “at around 36 °C, close to human body temperature, making it an ideal ‘smart’ candidate for applications in biomedicine and life sciences” (pg. 511, right column, para. 1 - pg. 512, left column, para. 1).
Schlaad expands on the “smart” behavior of polyoxazolines, teaching that they can change properties upon a change in solution temperature, pH, or ionic strength (pg. 517, left column, para. 1). Poly(2-alkyl-2-oxazoline)s with C2 and C3 side chains in particular are taught to have ideal LCSTs for applications involving the human body (pg. 517, Thermo-Responsiveness, para. 1). Schlaad further teaches that the LCST can be adjusted from 25-100 °C by variation of polymer molecular weight and composition between different mixtures of alkyl chains (pg. 517, right column, para. 2). Finally, Schlaad teaches that a variety of sugars that can be conjugated to the smart polyoxazoline polymers, including hyaluronan, another name for hyaluronic acid (pg. 515, right col., penultimate para. and Fig. 3).
Kharkar teaches the design of biocompatible hydrogels which can be designed to be degradable or non-degradable, responsive to biological conditions, and with other modifiable characteristics for applications including bioactive molecule delivery, cell encapsulation, and tissue engineering (Abstract). Hyaluronic acid (HA) is taught to be an “inherently biocompatible and non-immunogenic” natural polymer that plays a role in many biological processes (pg. 7339, 3.1.1. Hyaluronic acid). Kharkar teaches that HA can be broadly functionalized to allow the formation of hydrogels and that “HA-based hydrogels have shown excellent potential for biomedical engineering applications, such as…controlled delivery” (pg. 7340, left col., final para.). Two particular examples are taught to use HA-based hydrogels to deliver growth factors, anti-inflammatory steroid drugs, and proteins and led Kharkar to conclude that HA hydrogels are “attractive candidates for tissue regeneration and sustained therapeutic delivery (pg. 7340, right col., para. 1). Other natural polymers taught to be suitable for hydrogel preparation include collagen, gelatin, and others (pg. 7342, 3.2.6. Other natural polymers).
Chitosan, the deacetylated derivative of the polysaccharide chitin, is also taught by Kharkar to have excellent cytocompatibility, tunable degradation kinetics, and antimicrobial properties, making hydrogels formed from chitosan “attractive candidates for engineering applications, including wound-healing, bioactive molecule delivery and soft tissue engineering” (pg. 7340, right column, final para.). Chitosan is further taught to contain a “large number of accessible hydroxyl and amine groups…[which] provide numerous possibilities to create hydrogels via chemical crosslinking” (pg. 7341, left column, para. 1). Kharkar teaches that the hydrogels can be formed in situ via incorporation of “new functionalities” along the backbone, such as Schiff base or Michael-type addition reactions, and that the resulting hydrogels can perform controlled delivery of drugs and other live cells (pg. 7341, left column, para. 1). In one example, researchers functionalized chitosan with methacrylate polymers to encapsulate neural cells, which displayed greater survivability and extensive growth as compared to those in agarose-based control hydrogels (pg. 7341, right column, para. 1 and Fig. 5). Finally, Kharkar teaches that chemical modifications of polymer backbones, varying the size/MW of biomacromolecules, and varying the concentration ratios of polymers and biomacromolecules allows modification of the hydrogel storage modulus (pg. 7348, left column, para. 1 - right column, para. 1 and pg. 7356, left column, para. 2).
It would have been prima facie obvious to a person of ordinary skill in the art, prior to the filing of the instant application, to modify the method of Aoi to utilize poly(2-alkyl-2-oxazoline) conjugated to a biomacromolecule to form hydrogels in view of the teachings of Tomoki, Schlaad, and Kharkar because combining prior art elements according to known methods to impart a known benefit yields predictable results. Aoi teaches a method of conjugating poly(2-alkyl-2-oxazoline)s to a partially deacetylated chitin biomacromolecule, which is analogous to chitosan, via an amino functional group, methods of varying the degree of substitution with the poly(oxazoline)s, and their thermoresponsive behavior, which can be modified via changes in side chains and variations in polymers. In view of the teachings of Tomoki, one of ordinary skill in the art would be motivated to use poly(2-alkyl-2-oxazoline)s conjugated to chitin-derivatives to form hydrogels because Tomoki teaches that a biomacromolecule conjugated to poly(2-isopropyl-2-oxazoline) has the potential to form a hydrogel for drug delivery, providing an application that an ordinary artisan would recognize as useful. Further, the ordinary artisan would be motivated to use a biomacromolecule-thermoresponsive conjugate with the molecular weight and concentration taught above because Tomoki teaches that the resulting storage modulus would be appropriate for use in drug delivery.
In view of the teachings of Schlaad, a person of ordinary skill would be motivated to use the biomacromolecule-poly(2-alkyl-2-oxazoline)s in biomedicine and life science applications because Schlaad teaches that the oligomers exhibit behavior that can be manipulated via design modifications to operate near the temperature of the human body, “opening the way to stimulus-responsive materials and complex colloidal structures in aqueous environments”. In particular, Schlaad teaches that when the alkyl group in the poly(2-alkyl-2-oxazoline) is an isopropyl group, the corresponding polymer has an LCST at “around 36 °C, close to human body temperature”, which makes it in particular an ideal ‘smart’ candidate for biomedicine applications. The person of ordinary skill would be motivated to use the method of Aoi with (2-isopropyl-2-oxazoline)s in view of the teachings of Schlaad because there is a clear application for the resulting product.
In view of the teachings of Kharkar, an ordinary artisan would be motivated to modify the backbone of chitosan via its large number of amine and hydroxyl groups, as well as varying the size/MW and concentration ratio with respect to the polyoxazoline(s) because Kharkar teaches such modifications to enable artisans to manipulate properties such as degradation kinetics and storage modulus, which Schlaad and Tomoki previously taught to be relevant to hydrogel applications in biological contexts. Finally, one of ordinary skill in the art would find it obvious to use hyaluronic acid as the biomacromolecule conjugated to a polyoxazoline polymer because both Schlaad and Kharkar teach it to be a biocompatible polymer, Schlaad teaches HA to be capable of conjugation to polyoxazoline polymers, and Kharkar teaches hydrogels formed from HA to be attractive candidates for drug delivery.
"[I]nherency may supply a missing claim limitation in an obviousness analysis." PAR, 773 F.3d at 1194-1195; see also Endo Pharms. Sols., Inc. v. Custopharm Inc., 894 F.3d 1374, 1381, 127 U.S.P.Q.2D (BNA) 1409 (Fed. Cir. 2018). It is long settled that in the context of obviousness, the "mere recitation of a newly discovered function or property, inherently possessed by things in the prior art, does not distinguish a claim drawn to those things from the prior art." In re Oelrich, 666 F.2d 578, 581 (C.C.P.A. 1981). The Supreme Court explained long ago that "[i]t is not invention to perceive that the product which others had discovered had qualities they failed to detect." Gen. Elec. Co. v. Jewel Incandescent Lamp Co., 326 U.S. 242, 249, 66 S. Ct. 81, 90 L. Ed. 43, 1946 Dec. Comm'r Pat. 611 (1945).
Inherency, however, is a "high standard," that is "carefully circumscribed in the context of obviousness." PAR, 773 F.3d at 1195. Inherency "may not be established by probabilities or possibilities," and "[t]he mere fact that a certain thing may result from a given set of circumstances is not sufficient." Oelrich, 666 F.2d at 581 (emphasis added) (quoting Hansgirg v. Kemmer, 102 F.2d 212, 214, 26 C.C.P.A. 937, 1939 Dec. Comm'r Pat. 327 (C.C.P.A. 1939); see also In re Rijckaert, 9 F.3d 1531, 1533-1534 (Fed. Cir. 1993). Rather, inherency renders a claimed limitation obvious only if the limitation is "necessarily present," or is "the natural result of the combination of elements explicitly disclosed by the prior art." PAR, 773 F.3d at 119511-96; see also Alcon Research, Ltd. v. Apotex Inc., 687 F.3d 1362, 1369 (Fed. Cir. 2012) (relying on inherency where the claims recited "a property that is necessarily present" in the prior art). "If . . . the disclosure is sufficient to show that the natural result flowing from the operation as taught would result in the performance of the questioned function, it seems to be well settled that the disclosure should be regarded as sufficient" to render the function inherent. Oelrich, 666 F.2d at 581 (quoting Hansgirg v. Kemmer, 102 F.2d 212, 214, 26 C.C.P.A. 937, 1939 Dec. Comm'r Pat. 327 (C.C.P.A. 1939)). See MPEP § 2112.
In Persion Pharms. LLC v. Alvogen Malta Operations LTD., 945 F.3d 1184, 1191, 2019 USPQ2d 494084 (Fed. Cir. 2019), Persion contended that the district court erred in applying the inherency doctrine in its obviousness analysis because prior art reference Devane does not teach administering its hydrocodone-only formulation to patients with mild or moderate hepatic impairment. Thus, Persion asserts, "'the natural result flowing from the operation as taught' in Devane cannot be the claimed [pharmacokinetic] values for [hepatically impaired] patients." Appellant's Br. 37 (quoting Oelrich, 666 F.2d at 581); Reply Br. 19.
To the extent Persion contends that inherency can only satisfy a claim limitation when all other limitations are taught in a single reference, that position is contrary to the court’s prior recognition that "inherency may supply a missing claim limitation in an obviousness analysis" where the limitation at issue is "the natural result of the combination of prior art elements." PAR, 773 F.3d at 1194-1195 (emphasis added, internal quotations omitted). Here, the district court specifically found that Devane, together with Jain, the state of the prior art at the time of invention, and the Vicodin and Lortab labels, taught the combination of elements that inherently result in the claimed pharmacokinetic parameters. The district court found that a person of ordinary skill in the art would have been motivated, with reasonable expectation of success, to administer an unadjusted dose of the Devane formulation to hepatically impaired patients. There was also no dispute that the Devane formulation, which was identical to the Zohydro ER formulation described in the patents in suit, necessarily exhibited the claimed parameters under these conditions. Pernix, 323 F. Supp. 3d at 607, 610. In this context, the district court did not err by finding that the pharmacokinetic limitations of the asserted claims were inherent and added no patentable weight to the pharmacokinetic claims.
Because the thermoresponsive polymer conjugate, containing a polyoxazoline polymer and conjugated polysaccharide in the weight and degree of polymerization recited in instant claim 1, has been rendered obvious by the teachings above, the recited gelation temperature, LCST, and reversibility are necessarily present. As a result, there is a reasonable expectation of success in arriving at the method of claims 1-3, 5-6, and 8-12 in view of the teachings of Aoi, Tomoki, Schlaad, and Kharkar.
Claims 13-15 are rejected under 35 U.S.C. 103 as being unpatentable over Aoi (Macromol. Chem. Phys. 1994, 195 (12), 3747., provided by Applicant in IDS filed on 11 July 2025) in view of Tomoki (J. Mat. Chem. B 2019, 7, 6362., provided by Applicant in IDS filed on 10 March 2023), Schlaad (Macromol. Rapid Commun. 2010, 31 (6), 507.), and Kharkar (Chem. Soc. Rev. 2013, 42, 7335.) as applied to claims 1-3, 5-6, and 8-12 above, and further in view of Hirt et al. (U.S. Patent Application Publication No. US 2008/0260833 A1, published on 23 October 2008, hereafter referred to as Hirt).
Aoi, Tomoki, Schlaad, and Kharkar teach the above, and particularly relevant to instant claims 14 and 15, Schlaad teaches poly(oxazoline)s with LCSTs around 36 °C are ideal ‘smart’ candidates for applications in biomedicine and life sciences, Tomoki teaches that their poly(oxazoline)-carbohydrate polymer hydrogel may be used for the encapsulation and delivery of drugs, and Kharkar teaches the biocompatibility and applications of chitosan-based hydrogels.
Aoi, Tomoki, Schlaad, and Kharkar do not teach a drug, microparticles, and/or nanoparticles to be encapsulated within a hydrogel during hydrogel formation, nor the type of biologically active agent encapsulated. These deficiencies are offset by the teachings of Hirt.
Hirt teaches a “drug delivery vehicle having active agent loaded vesicles in a hydrogel matrix” (Abstract). Preferred delivery mechanisms are taught to be “made at least partially of a stimulus responsive polymer so that release of the active agent from the vesicles, and the vehicle, is triggered by exposure to the stimulus” (para. [0003]). Hirt teaches that active agents can be encapsulated via different methods, including that “the agent may be directly added to the copolymer during preparation of the copolymer” (para. [0060]). In a preferred embodiment, the hydrogels are taught to self-assemble to form “hollow particles” in water (para. [0034]). In some embodiments, the polymers encapsulating the active agents may be co-polymers comprising poly(2-alkyl-2-oxazoline) (Examples 1 and 4-5). Examples of active agents that may be encapsulated and subsequently delivered by the invention of Hirt include antibiotics, antivirals, vasoactive compounds, vaccines, local anesthetics, and nanoparticles (para. [0058-0059]).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the filing date of the instant application, to combine the teachings of Hirt with the method rendered obvious by the teachings of Aoi, Tomoki, Schlaad, and Kharkar to arrive at the method of claims 13-15 because combining prior art elements according to known methods yields predictable results. An ordinary artisan would be motivated to combine the teachings of Hirt with the invention rendered obvious above because neither Schlaad nor Tomoki provide specific examples of drugs or biomedicines to be delivered by their hydrogels. Hirt provides many useful examples of drugs, nanoparticles, and other therapeutic agents that can be delivered by the thermoresponsive polymer biomacromolecule conjugates rendered obvious above and a person of ordinary skill would recognize the utility in encapsulating those molecules and/or nanoparticles within their hydrogel. In addition, neither Schlaad nor Tomoki provide specific synthetic steps to encapsulate drugs in their hydrogel, while Hirt teaches that the drug may be added directly to the polymer solutions during preparation. As a result, there is a reasonable expectation of success in arriving at the method of claims 13-15 in view of the teachings of Aoi, Tomoki, Schlaad, and Kharkar and further in view of the teachings of Hirt.
Response to Arguments
The Applicant’s arguments, filed on 26 May 2026, have been fully considered but are not persuasive.
Applicant argues from para. 2 of pg. 8 to para. 1 of pg. 11 that the teachings of Aoi, Tomoki, Schlaad, and Kharkar would not render obvious a hydrogel, formed from a thermoresponsive polymer-biomacromolecule conjugate, that is thermoreversible because thermoreversible behavior is not inherent to a thermoresponsive polymer-biomacromolecule conjugate.
As stated above, inherency is a "high standard" that is "carefully circumscribed in the context of obviousness." PAR, 773 F.3d at 1195. Inherency "may not be established by probabilities or possibilities," and "[t]he mere fact that a certain thing may result from a given set of circumstances is not sufficient." Oelrich, 666 F.2d at 581 (emphasis added) (quoting Hansgirg v. Kemmer, 102 F.2d 212, 214, 26 C.C.P.A. 937, 1939 Dec. Comm'r Pat. 327 (C.C.P.A. 1939); see also In re Rijckaert, 9 F.3d 1531, 1533-1534 (Fed. Cir. 1993). Rather, inherency renders a claimed limitation obvious only if the limitation is "necessarily present," or is "the natural result of the combination of elements explicitly disclosed by the prior art." PAR, 773 F.3d at 119511-96; see also Alcon Research, Ltd. v. Apotex Inc., 687 F.3d 1362, 1369 (Fed. Cir. 2012). "If . . . the disclosure is sufficient to show that the natural result flowing from the operation as taught would result in the performance of the questioned function, it seems to be well settled that the disclosure should be regarded as sufficient" to render the function inherent. Oelrich, 666 F.2d at 581 (quoting Hansgirg v. Kemmer, 102 F.2d 212, 214, 26 C.C.P.A. 937, 1939 Dec. Comm'r Pat. 327 (C.C.P.A. 1939)). See MPEP § 2112.
Instant claim 1 recites a method with the steps of i) preparing a thermoresponsive polymer, which in one embodiment is a polyoxazoline polymer, with a molecular weight of 5-100 kDa via living cationic ring opening polymerization; and ii) reacting the living cation with a functional group, which may be a carboxylate, amino, sulfate, sulfonate, phosphate, phosphonate, or thiol group, of a biomacromolecule, which may be HA, gelatin, or collagen, at a degree of substitution of 5-30%. Claim 1 further recites that, in an aqueous liquid, the so-formed thermoresponsive polymer biomacromolecule conjugate exhibits the recited gelation temperature.
A biomacromolecule-thermoresponsive polymer conjugate containing a polyoxazoline polymer in the weight recited in instant claim 1 and HA and possessing a degree of polymerization recited in instant claim 1, prepared via the claimed method, has been rendered obvious (vide supra). No manipulative steps are recited in instant claim 1 that have not been rendered obvious above and Applicant recited in claim 1 that the biomacromolecule-thermoresponsive polymer conjugate possesses the claimed properties. Therefore, the Examiner maintains that the recited gelation temperature, LCST, and reversibility are necessarily present.
The MPEP states in § 2112.IV. that the Examiner “must provide rationale or evidence to show inherency”. The argument above is considered to be rationale that the recited properties are inherent. The MPEP subsequently states in § 2112.V. that once “the Examiner presented evidence or reasoning to show inherency, the burden of production shifts to the Applicant”. "[T]he PTO can require an applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his [or her] claimed product. Whether the rejection is based on ‘inherency’ under 35 U.S.C. 102, on ‘prima facie obviousness’ under 35 U.S.C. 103, jointly or alternatively, the burden of proof is the same." In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433-34 (CCPA 1977). Applicant has not proven that the method rendered obvious by the prior art above does not necessarily or inherently possess the claimed gelation temperature, LCST, and reversibility, therefore the properties are maintained to be necessarily present and the argument is not found to be persuasive.
In response to Applicant's arguments against the Aoi, Tomoki, Schlaad, and Kharkar references individually from para. 2 of pg. 11 to the final para. of pg. 12, Applicant is reminded that 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).
In the section titled “Regarding Aoi” on pg. 11, Applicant argues that the Aoi reference does not teach the biomacromolecule to be hyaluronic acid, gelatin, or collagen and that the chitosan backbone taught by Aoi is different from the biomacromolecule backbones recited in the claimed method. The claims considered in the Office Action mailed on 27 January 2026, did not limit the biomacromolecule to be hyaluronic acid, gelatin, or collagen and the limitation could not be considered, therefore the argument is found to be unpersuasive. The new grounds of rejection above, necessitated by the amendments filed on 26 May 2026, argue that substituting the chitosan taught by Aoi with hyaluronic acid would be obvious in view of the teachings of Schlaad and Kharkar regarding the polymer, in particular its biodegradability, ability to form hydrogels, and suitability for drug delivery.
In the section titled “Regarding Tomaki” spanning pg. 11-12, Applicant argues that the Tomaki reference does not teach a biomacromolecule-polymer conjugate with a gelation temperature of 4-45 °C. Neither the rejection in the previous Office Action nor the rejection above argue that the Tomaki reference teaches the argued property. As argued in the rejection above, this property is considered inherent to the claimed structure of a polyoxazoline polymer with a molecular weight of 5-100 kDa, prepared via living cationic ring polymerization, conjugated to a biomacromolecule that is hyaluronic acid, gelatin, or collagen at a degree of substitution between 5-30% via a carboxylate, amino, sulfate, sulfonate, phosphate, phosphonate, or thiol group. Because a biomacromolecule-polymer conjugate prepared via the claimed method has been rendered obvious, the property is necessarily present as well and the argument is not found to be persuasive.
In the section titled “Regarding Schlaad and Kharkar” on pg. 12, Applicant argues that the Schlaad reference does not teach hydrogels formed from HA, gelatin, or collagen conjugates nor that “copolymer architecture” is required to achieve the claimed properties. The Schlaad reference was not used for its teachings regarding hydrogels from HA, gelatin, or collagen nor copolymer architecture in the previous Office Action, and on the contrary, Schlaad does teach the conjugate of a polyoxazoline polymer and HA, which the ordinary artisan would recognize as capable of forming a hydrogel. Also in this section, Applicant argues that the Kharkar reference does not teach living-cation conjugation chemistry or temperature related properties. The Kharkar reference was not argued to teach these things but was instead used for its teachings regarding biocompatible hydrogels, including HA, gelatin, collagen, and chitosan, and their suitability for drug delivery. As a result, Applicant’s arguments are found to be unpersuasive.
From para. 1 of pg. 13 to para. 2 of pg. 14, Applicant restates their argument that the gelation temperature, LCST, and thermoreversibility are not inherent properties of the thermoresponsive polymer biomacromolecule conjugate. This argument has been addressed above.
In para. 3 of pg. 14, Applicant argues that overlapping ranges or values taught within ranges recited in the instant claims do not render obvious the ranges in the instant claims because “the art does not teach that the parameter in question is result-effective in the relevant system” (emphasis quoted). The MPEP states in § 2144.05.C that “Applicants may rebut a prima facie case of obviousness based on optimization of a variable disclosed in a range in the prior art by showing that the claimed variable was not recognized in the prior art to be a result-effective variable.” E.I. Dupont de Nemours & Company v. Synvina C.V., 904 F.3d 996, 1008, 128 USPQ2d 1193, 1202 (Fed. Cir. 2018). “Applicants must articulate why the variable at issue would not have been recognized in the prior art as result-effective.”
Applicant’s statement in para. 3 of pg. 13 that “the specification shows that small changes in degree of substitution or copolymer composition can switch the system from gelation to non-gelation or precipitation” is interpreted as an articulation that the prior art does not recognize the degree of substitution or molecular weight of polymers to be result-effective variables. Aoi teaches that the degree of substitution impacts the polymer number-average molecular weight (Table 1) and solubility (Table 2) and is considered a recognition that degree of substitution is a result-effective parameter. Kharkar teaches that molecular weight inhomogeneity can “dramatically reduce the mechanical strength of hydrogels (Kharkar, pg. X, 4.1.1 Radical polymerization) and that molecular weight can impact degradation rates of hydrogels (Kharkar, pg. X, 5.2.2 Hydrolytic degradation) and Schlaad teaches that the molecular weight of poly(2-isopropyl-2-oxazoline) polymers has a considerable impact on phase transition temperature, which is considered to be a recognition that molecular weight of polymers is a result-effective parameter. As a result, Applicant’s argument is found to be unpersuasive.
Finally, in the final para. of pg. 13 Applicant argues that the instant spec. demonstrates the criticality of multiple parameters including degree of substitution. This is considered a claim of unexpected results. Guidelines on determining whether results are expected or unexpected are provided in MPEP § 716.02 and were discussed in the previous Office Action. Repeated here in brief for convenience, to demonstrate that results are unexpected and significant, the Applicant has the responsibility of presenting evidence that establishes “that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance.” Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992). “Evidence of unexpected properties may be in the form of a direct or indirect comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims” (bold added for emphasis). See In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980) and MPEP § 716.02(d) - § 716.02(e). As stated in the previous Office Action, the Applicant has not persuasively demonstrated evidence of unexpected and unobvious properties and because further evidence has not been presented here, the claim of unexpected results is still not found to be persuasive.
Conclusion
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Schanté et al. (Carbohydr. Polym. 2011, 85, 469.) teach a review of chemical modifications that can be made to hyaluronic acid to enable usage in a broad range of biomedical applications (Abstract), including drug delivery (4. HA derivatives, pg. 479-484) in the form of hydrogels (4.1. HA hydrogels for supplementation, pg. 479-480 and 5.3. Physical characterization, pg. 485-485).
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 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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/S.J.S./
Examiner, Art Unit 1619
/DAVID J BLANCHARD/Supervisory Patent Examiner, Art Unit 1619
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