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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 19 December 2025, has been entered.
Status of Claims
The amendments, filed on 19 December 2025, are acknowledged.
Claims 1 and 8 are amended.
Claims 1-3, 5-6, and 8-15 are pending and under consideration in the instant Office Action.
Withdrawn Rejections
Rejections pursuant to 35 U.S.C. § 103
The rejections of claims 1-3, 5-6, and 8-15 under 35 U.S.C. § 103 presented in the final Office Action, mailed on 25 September 2025, are withdrawn in view of Applicant’s amendment to the claims and in favor of the new grounds of rejection below.
New Grounds of Objection/Rejection
Objection to title
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed. The title of the instant application is “HYDROGELS”. The title should be brief but technically accurate and descriptive and should contain fewer than 500 characters. The title does not reflect the main inventive concept of Applicant’s invention and the major components of the invention. The title is generic and can be applicable to any “hydrogels”. The Examiner advises Applicant to consider including major components of the composition, primary purpose of the invention, and/or the general steps taken to achieve the claimed invention in the title to precisely reflect the inventive concept. Inasmuch as the words "new", "improved", "improvement of", and "improvement in" are not considered as part of the title of an invention, these words should not be included at the beginning of the title of the invention and will be deleted when the Office enters the title into the Office’s computer records, and when any patent issues. Similarly, the articles "a," "an," and "the" should not be included as the first words of the title of the invention and will be deleted when the Office enters the title into the Office’s computer records, and when any patent
issues.
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, 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). Finally, 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. Finally, 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).
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). Chitosan, the deacetylated derivative of the polysaccharide chitin, is taught 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. Finally, 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.
"[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 19 December 2025, have been fully considered but are not persuasive.
In response to Applicant's arguments against the Aoi, Schlaad, and Tomoki references individually, 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).
From para. 2 of pg. 8 of the Remarks filed on 19 December 2025, to para. 1 of pg. 9, Applicant argues that the Aoi reference does not teach the existence of hydrogels. The rejection above relies upon the combination of Aoi with Tomoki, Schlaad, and Kharkar, and the absence of information in one reference is not a persuasive argument against the combination. See MPEP § 2145.IV.
In para. 2 of pg. 9, Applicant argues that a person of ordinary skill in the art would not look to Aoi regarding the degree of substitution of a polymer nor the LCST and gelation temperatures. The rejection above relies upon the teachings of Aoi regarding a poly(2-alkyl-2-oxazoline) polymer that is conjugated to a biomacromolecule and its deficiencies with respect to teaching the limitations of the instant claims is addressed above with the teachings of Tomoki, Schlaad, and Kharkar.
In the final two para. of pg. 9, Applicant argues that a person of ordinary skill would not combine the teachings of Aoi and Schlaad and that using the teachings of Schlaad regarding gelation temperature requires impermissible hindsight. This argument is now considered moot in view of the newly presented rejection above, in particular the argument regarding the inherency of a gelation temperature, LCST, and reversible gelling of a thermoresponsive polymer conjugate containing a polyoxazoline polymer and conjugated polysaccharide in the weight and degree of polymerization recited in instant claim 1.
From para. 2 of pg. 9 to para. 1 of pg. 11, Applicant argues that the Schlaad reference does not teach hydrogels, but rather crystallization of their biopolymers, and that the LCST “cannot be interpreted to mean the relevant polymer system has any ability to form a hydrogel, nor that the LCST is functionally equivalent to a gelation temperature”. Again this argument is considered moot in view of the newly presented rejection above (vide supra).
In the second para. of the Regarding Tomoki section of pg. 11, Applicant argues that the synthetic pathway of Tomoki is entirely different and only enables one sugar to be conjugated to each polyoxazoline polymer. The Examiner respectfully disagrees, as the limitations of instant claim 1 require the preparation of a thermoresponsive polymer, which may polyoxazoline, via living cationic ring opening polymerization, conjugated to a biomacromolecule via a nucleophilic functional group, which may be amine. These limitations are taught by the Aoi reference, which uses living cationic ring opening polymerization to create poly(2-alkyl-2-oxazoline) and conjugates the polymer to a polysaccharide via an amino group. Further, instant claim 1 recites the thermoresponsive polymer to be conjugated to the biomacromolecule at a degree of substitution from 5-30%, which is also taught by the Aoi reference (vide supra). The Tomoki reference similarly teaches living cationic ring opening polymerization of poly(2-alkyl-2-oxazoline), which is subsequently conjugated to a mono- or polysaccharide. The ability to conjugate the polymer to more than one sugar is not recited in the instant claims and would be obvious in view of the teachings of Kharkar regarding the “large number of accessible hydroxyl and amine groups in chitosan [which] provide numerous possibilities to create hydrogels via chemical crosslinking”.
From para. 3 of the Regarding Tomoki section of pg. 11 to the top of pg. 12, Applicant argues that the molecular weight taught by Tomoki refers only to the overall conjugate (polymer and biomacromolecule) and does not motivate one of ordinary skill to limit the molecular weight of the polymer. This is not persuasive because Tomoki explicitly teaches the carbohydrates in Scheme 1 to be glucose (MW ~180 Da), maltotriose (three glucose molecules, MW ~504 Da), or maltopentaose (five glucose molecules, MW ~900 Da). Simple subtraction results in a MW that is still ~13-14 kDa, which falls within the recited range.
From para. 2 of pg. 12 to para. 2 of pg. 13, Applicant argues that the reversible gelation of the polymer, gelation temperature, and LCST temperature are not taught by the Tomoki reference. Again this argument is against one reference whereas the rejection above relies upon the combination of Aoi with Tomoki, Schlaad, and Kharkar. The absence of information in one reference is not a persuasive argument against the combination. See MPEP § 2145.IV.
In the Regarding Aoi, Schlaad, and Tomoki section that spans pg. 13-14, Applicant argues that the Aoi and Schlaad references would not have “led a person of ordinary skill in the art to [the] claimed polymer systems that can form hydrogels” in the antepenultimate para. of pg. 13. As stated above, the previously presented rejection was based upon the combination of the Aoi, Schlaad, and Tomoki references, and piecemeal analysis of the references is not persuasive.
Applicant also argues in the antepenultimate para. of pg. 13 that the Tomoki reference does not teach the reversibility of gelation nor the temperature. As stated above, this argument is considered moot in view of the newly presented rejection above, in particular the argument regarding the inherency of a gelation temperature, LCST, and reversible gelling of a thermoresponsive polymer conjugate containing a polyoxazoline polymer and conjugated polysaccharide in the weight and degree of polymerization recited in instant claim 1.
In the penultimate para. of pg. 13, Applicant argues that the limitations of the instant claims cannot be reached without impermissible hindsight. In response to Applicant's argument, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). The Examiner respectfully disagrees, as the instant claims require the preparation of a thermoresponsive polymer, which may be polyoxazoline, via living cationic ring opening polymerization, conjugated to a biomacromolecule via a nucleophilic functional group, which may be amine. These limitations are taught by the Aoi reference, which uses living cationic ring opening polymerization to create poly(2-alkyl-2-oxazoline) and conjugates the polymer to a polysaccharide via an amino group. Further, instant claim 1 recites the thermoresponsive polymer to be conjugate to the biomacromolecule at a degree of substitution from 5-30%, which is also taught by the Aoi reference. The limitation regarding the molecular weight of 5-100 kDa is addressed by the combination of the Tomoki reference with Aoi, and their combination would be motivated because both references teach polyoxazoline polymers conjugated to biomacromolecules and the Tomoki reference specifically teaches additional properties of the conjugates. The reversible gelation of the polymer, gelation temperature, and LCST temperature are rejected above as being inherent to the claimed structure (vide supra).
Finally, in the para. that spans the end of pg. 13 and top of pg. 14, Applicant claims that they have found unexpected results that would have been “unexpected to a person of ordinary skill in the art”. Guidelines on determining whether results are expected or unexpected are provided in MPEP § 716.02. 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).
The Applicant has compared their claimed method to other methods in Comparative Examples C1-C5, specifically by varying the nucleophilic functional group (Example C1), chemical conjugation vs physical mixing (Example C2), release kinetics of chemical conjugation vs physical mixing (Example C3), varying the specific amine-containing molecule (Example C4), and indirect conjugation via 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)/N-Hydroxysuccinimide (NHS) coupling (Example C5). A comparison to the closest prior art would include a comparison to Aoi, which teaches a thermoresponsive polymer prepared via living cationic ring opening polymerization with the same monomer recited in the instant application, conjugated to the polysaccharide chitosan as compared to hyaluronic acid as in instant Examples 1-4, with overlapping ranges of degrees of substitution, or a comparison to Tomoki, which teaches hydrogels formed from thermoresponsive polymers prepared via living cationic ring opening polymerization with the same monomer recited in the instant application, conjugated to glucose polysaccharides as compared to hyaluronic acid as in instant Examples 1-4, modifications to the storage modulus of the hydrogels, and the encapsulation of drugs within the hydrogels.
Further, the claimed demonstration of unexpected results does not outweigh the strength of the prima facie case of obviousness because the method steps recited in the instant claims, such as the monomers used in living cationic ring opening polymerization, the degree of substitution used, the identity of the biomacromolecule used, the identity of the nucleophilic functional group on the biomacromolecule, etc. are taught by the prior art references above. The claimed unexpected result of a hydrogel formed from a thermoresponsive polymer conjugated to a biomacromolecule with reversible gelation in the range of 4-45 °C would necessarily be achieved by a person of ordinary skill in the art in view of the teachings of the prior art. Applicant is reminded that "The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious." Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). Mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. In re Wiseman, 596 F.2d 1019, 201 USPQ 658 (CCPA 1979), see MPEP 2145. Although the record may establish evidence of secondary considerations which are indicia of nonobviousness, the record may also establish such a strong case of obviousness that the objective evidence of nonobviousness is not sufficient to outweigh the evidence of obviousness. Newell Cos. v. Kenney Mfg. Co., 864 F.2d 757, 769, 9 USPQ2d 1417, 1427 (Fed. Cir. 1988). See MPEP § 716.01(d). As a result, the claim of unexpected results is not found to be persuasive.
Conclusion
No claims are allowed.
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/S.J.S./
Examiner, Art Unit 1619
/DAVID J BLANCHARD/Supervisory Patent Examiner, Art Unit 1619