Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Claim Status
Claims 1-8 are pending and under consideration.
Election/Restrictions
Applicant’s election without traverse of Group 1, claims 1-4, in the reply filed on 08 May 2026 is acknowledged. Applicants also elected that the first click chemistry functional group is methyltetrazine-PEG4-amine, the second click chemistry functional group is trans-cyclooctene-amine, and that the drug is doxorubicin in response to the species election requirement.
Claims 5-8 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention.
Claims 1-4 are under consideration to the extent of the elected species, i.e., that the first click chemistry functional group is methyltetrazine-PEG4-amine, the second click chemistry functional group is trans-cyclooctene-amine, and that the drug is doxorubicin.
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. 17/053,429, filed on 06 Nov 2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 24 May 2024 is in compliance with the provisions of 37 CFR 1.97, except where noted. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 3 and 4 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites the limitation "the cyclooctene groups" in step (d). There is insufficient antecedent basis for this limitation in the claim as cyclooctene groups are not referenced in the claim. Claims 3 and 4 are included in this rejection as they depend directly, indirectly, or include all the limitations of independent claim 1.
Claim 1 is indefinite in the recitation of “the state where tetrazine groups and the cyclooctene groups are chemically linked.” Tetrazine and cyclooctene are understood to be potential first and second click chemistry functional groups (e.g. see claim 2) but claim 1 does not specify the first and second click chemistry functional groups as tetrazine and cyclooctene. It is unclear if step (d) is intended to require that the tetrazine is the first or second functional group or if the cyclooctene is the first or second functional group or whether the tetrazine and cyclooctene represent groups in addition to the first and second functional groups. Claims 3 and 4 are included in this rejection as they depend directly, indirectly, or include all the limitations of independent claim 1.
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 1-4 are rejected under 35 U.S.C. 103 as being unpatentable over Kim et al. (Adv. Healthcare Mater. 2016, 5, 3105–3117, listed on IDS filed 05/24/2024) as evidenced by the instant specification and in view of Kim et al. (WO 2016/209062, published 29 Dec 2016, referred to herein as Kim#2, listed on IDS filed 05/24/2024), No et al. (WO2017/057824, published 06 Apr 2017) and Desai et al. (US2017/0189581, published 06 Jul 2017, filed 06 Apr 2015, listed on IDS filed 05/24/2024).
Kim teaches an injectable hydrogel of small intestine submucosa (SIS) formed from the click chemistry reaction between functional groups tetrazine and transcyclooctene (see entire document, abstract, 1. Introduction). As evidenced by the instant specification, SIS is a biopolymer (page 8 third paragraph). Preparations of tetrazine-modified SIS (TE-SIS) and transcyclooctene modified SIS (TC-SIS) were individually prepared and then click-cross-linked by mixing equal amounts of TE-SIS and TC-SIS suspensions (2.1 Preparation of Injectable SIS Formulations), rendering obvious preparing a first and second liquid with click chemistry functional groups and biopolymer and reacting the first and second liquid as claimed. Kim teaches that the specific tetrazine was tetrazine-PEG-NHS ester (section 2.1, section 4). Kim teaches that injectable hydrogels are ubiquitously used as drug carriers (page 3105 col 2 paragraph 1) and teaches that the hydrogel may comprise the drug methotrexate by loading methotrexate into the TE-SIS and TC-SIS solutions prior to reacting (abstract, 4. Preparation of Met-Loaded SIS, Met-Loaded TE-SIS, or Met-Loaded TC-SIS Suspension). Kim teaches that the cross linked SIS displayed extensive regeneration of chondrocytes and glycosaminoglycan deposits (abstract) and successfully supported the regeneration of cartilage tissue in vivo (page 3112 left column, page 3114 right column). Regarding claim 3, Kim teaches the reaction of DMTMM with the TE-SIS or TC-SIS (page 3115 left column middle). As evidenced by the instant specification, DMTMM is a condensing agent (page 11 middle), and thus the inclusion of DMTMM renders obvious claim 3.
Regarding the mechanical properties of the injectable of claim 1, Kim teaches that the mechanical properties for injectable SIS formulations were analyzed by rheology with a change in frequency from 0.1 to 10 Hz (page 3106 2.2 Characterization of SIS and Cx-SIS) and teaches analyzing properties including storage modulus and viscosity (Figure 3). Kim teaches that the crosslinked SIS exhibited higher storage modulus and viscosity than the non-crosslinked SIS (page 3106 2.2 Characterization of SIS and Cx-SIS).
While Kim teaches tetrazine-PEG-NHS ester and transcyclooctene, Kim does not teach the elected species of functional groups methyltetrazine-PEG4-NHS and transcyclooctene amine. Further, Kim does not teach the storage modulus, complex viscosity and swelling ratio properties as recited in claim 1. Kim does not teach the hydrogel is in porous form (claim 4). These deficiencies are made up for in the teachings of Kim#2, No, and Desai.
Kim#2 teaches a two-component bioink for a 3D biomaterial including a first solution and a second solution separately, wherein the first solution includes a first biopolymer to which a first chemical functional group is introduced, and the second solution includes a second biopolymer to which a second chemical functional group able to chemically bond with the first chemical functional group is introduced ([10], [13]). Kim#2 teaches biopolymers including small intestinal submucosa ([44], [46]). Regarding the species of functional groups, Kim#2 teaches that materials having a first chemical functional group include methyltetrazine-PEG4-amine ([45]) and materials having a second functional group include trans-cyclooctene-amine ([47]). Kim#2 teaches that the bioink may be applied to various 3D biomaterial fields such as a tissue-engineered scaffold, a drug carrier or an anti-adhesive agent ([9], [15]). Kim#2 teaches that scaffolds need to be a porous structure to facilitate three dimensional cell growth, exchange nutrients and excretions, and have biodegradation according to tissue regeneration rate, mechanical strength to keep a shape during regeneration, and excellent biological safety ([3]).
No teaches a polyethylene glycol hydrogel injection ([1]) where the complex viscosity of the hydrogel may have an initial value ranging from 0.01 to 1 Pa•s and may range from 4 to 1,000 Pa•s at 2000 seconds or more ([78]). No teaches that the high viscosity can cause pain due to high injection force during administration into a joint and the low viscosity is achieved by controlling the duration of crosslinking and the excellent viscoelasticity after injection is attained as a result of gradually reacting to form PEG-hydrogels ([79]). No teaches varying the reaction conditions can be used to control the swelling ratio of a cross linked hyaluronic acid hydrogel ([7]). No describes a hyaluronic acid hydrogel in a 10 Hz condition with a storage modulus between 50-1,500 Pa as part of having superior viscoelasticity ([9]).
Desai teaches that hydrogels are polymer gels comprising a network of crosslinked polymer chains and have uses including tissue engineering as scaffolding, small molecule delivery, and structural materials ([0003]). Desai teaches obtaining hydrogels with the desired physicochemical/mechanical properties such as elasticity, strength, swelling extent, and degradation rate ([0003]). Desai teaches forming biocompatible hydrogels using biorthogonal click chemistry ([0004]). Desai teaches controlling the mechanical properties such as elasticity and strength, swelling ratios and degradation profiles of the hydrogel and that hydrogel mechanical characteristics can be tuned through manipulation of the polymer molecular weight, degree of click substitution, and/or stoichiometery of the click chemistry components ([0107]). Desai teaches click cross linked hydrogels are advantageous as injectable hydrogels where they are a flowable composition that forma a gel in the body after injection ([0107]). Desai teaches the hydrogel as elastic with a Young’s modulus from about 50 to about 50,000 Pa ([0066]) and teaches monitoring the storage modulus ([0160]). Desai different concentration hydrogels with different storage modulus values (Fig 7B, [0177]). Desai teaches that the swelling ratio of hydrogel systems can affect the mechanical properties, mass transport, and the presentation of ligands on the gel surface ([0164]).
Therefore, it would have been prima facie obvious to one of ordinary skill in the
art, before the effective filing date of the claimed invention to have formed a method of preparing an injectable hydrogel comprising reacting a solution of methyltetratzine-PEG4-NHS modified SIS and a solution of transcyclooctene amine SIS and to confirm the functional groups are linked with optimal values of mechanical properties such as storage modulus, complex viscosity, and swelling ratio and to have the hydrogel in a porous form. Injectable hydrogels of small intestine submucosa formed from the click chemistry reaction between functional groups tetrazine and transcyclooctene and their use as drug carriers and tissue regeneration are known from Kim. Similar compositions for tissue scaffolding and drug carriers comprising solutions of a biopolymer such as SIS and a first functional group such as methyltetrazine-PEG4-amine and a second functional group such as trans-cyclooctene-amine which are reacted to form a 3D biomaterial are known from Kim#2. Thus, methyltetrazine-PEG4-amine and trans-cyclooctene-amine are functional groups known for combining with biopolymers such as SIS reacting to form biomaterials, thereby rendering these groups as obvious tetrazine and transcyclooctene alternatives for reacting together and providing a reasonable expectation of success as they are known for linking biopolymers such as SIS together. It would be obvious to form the hydrogel with a porous structure as a porous structure facilitates properties including three dimensional cell growth and exchange of nutrients and excretions, and having biodegradation according to tissue regeneration rate, mechanical strength to keep a shape during regeneration, and excellent biological safety, as known from Kim#2. The hydrogels of Kim are known to support tissue regeneration and it would be obvious to have the hydrogel as a porous form for the benefits listed above. Regarding the confirmation of properties of storage modulus, complex viscosity, and swelling ratio, these would be obvious as a matter of routine experimentation, in view of the teachings of Kim, No, and Desai, as these properties are art-recognized result effective variables such that determining that the storage modulus is 200 Pa to 400 Pa, the complex viscosity is 30 Pa•s to 60 Pa•s, and the swelling ratio is 7500-10,000% would be a matter of optimization through routine experimentation. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Kim characterizes mechanical properties of storage modulus and viscosity of the injectable formulations by rheology, rendering it obvious to determine or confirm mechanical properties of the hydrogel. It is known from Desai that mechanical properties of hydrogels can be controlled and it is further known from Desai that it is desirable to achieve hydrogels with desired physicochemical/mechanical properties such as elasticity, strength, swelling extent and degradation rate. The complex viscosity of hydrogels may vary and lower viscosity is related to reduced injection pain and the viscosity is increased after injection to achieve excellent viscoelasticity, as known from No. Additionally, the storage modulus is a parameter that is varied as part of achieving desired viscoelasticity, as known from No and Desai. No further teaches complex viscosity values for injectable hydrogels ranging from 4 to 1,000 Pa•s and describes a storage modulus between 50-1,500 Pa, indicating these as suitable ranges for injected hydrogels. Further, it is known from Desai that the swelling ratio of hydrogel systems affects properties such as mechanical properties and mass transport. Thus, it is known from the art that mechanical properties such as complex viscosity, storage modulus, and swelling ratio may be measured and are variable parameters of hydrogels related to the performance and function of the hydrogel and it would have been obvious to one of ordinary skill in the art to determine optimal values for each of these properties and to confirm them in the hydrogel in order to achieve the desired injectable hydrogel characteristics.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-4 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 6-8 of U.S. Patent No. 10,894,895 in view of Kim et al. (Adv. Healthcare Mater. 2016, 5, 3105–3117, listed on IDS filed 05/24/2024) as evidenced by the instant specification, Kim et al. (WO 2016/209062, published 29 Dec 2016, referred to herein as Kim#2, listed on IDS filed 05/24/2024), No et al. (WO2017/057824, published 06 Apr 2017) and Desai et al. (US2017/0189581, published 06 Jul 2017, filed 06 Apr 2015, listed on IDS filed 05/24/2024).
The ‘895 patent recites a method for preparing a 3D biomaterial comprising preparing a first solution by adding a material having a first chemical function agroup to a first biopolymer, preparing a second solution by adding a material having a second chemical functional group able to bond with a first chemical function group to a second biopolymer and chemically combining the first solution with the second solution. The first chemical functional group may be methyltetratzine PEG4 amine and the second chemical functional group may be transcyclooctene amine.
The ‘895 patent does not recite the form of an injectable hydrogel or confirming the properties of storage modulus, complex viscosity, or swelling ratio and does not recite a condensing agent or a porous form. These differences are made up for in the teachings of Kim, Kim#2, No, and Desai.
The teachings of Kim, Kim#2, No, and Desai are described supra.
Therefore, it would have been prima facie obvious to one of ordinary skill in the
art, before the effective filing date of the claimed invention to have the method for preparing the 3D biomaterial modified to prepare an injectable hydrogel and to optimize the mechanical properties of storage modulus, complex viscosity, and swelling ratio and formed the hydrogel with DMTMM (a condensing agent) and in a porous form. The preparation of injectable hydrogels are known from Kim and are made using compatible tetratzine and transcyclooctene groups attached to SIS. As it is similar components combined in similar way to make a 3D material, it would be obvious to extend the method of preparing the 3D material of the reference patent to the preparation of an injectable hydrogel with a reasonable expectation of success. As known from Kim, No, and Desai, mechanical properties are measured by rheology and storage modulus, complex viscosity and swelling ratio are properties that affect the performance of a hydrogel and it would be obvious to optimize each of these parameters through routine experimentation for desired hydrogel performance. It is known from Kim that DMTMM is used in forming hydrogels with the functional groups listed above, rendering this an obvious component to include in the method of preparation. It is further known from Kim#2 that having materials as porous supports three dimensional cell growth, exchange of nutrients and excretions, biodegradation according to tissue regeneration rate, mechanical strength to keep a shape during regeneration, and biological safety, rendering it obvious to have the hydrogel in a porous form, for the reasons listed.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references.
Conclusion
No claim is allowed.
Correspondence
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/EDWIN COLEMAN MITCHELL/Examiner, Art Unit 1619
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