DETAILED ACTION
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 .
Status of the Claims
Claims 1-11 and 16 are pending and under current examination.
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 1-11 and 16 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 “silica having -Si-OH groups” in line 5 and also recites "the Si-OH groups of the silica form a -Si-O-Si- bond with the -Si-O3- group of the functionalized triblock" in line 8. This language renders the claim internally contradictory because, as it is currently worded, the claim requires two states for the pendant oxygens of the silica; however, an atom cannot simultaneously be in the form of a free hydroxyl and also bound by two covalent bonds to separate silicon atoms, as depicted in the claim. To overcome the rejection, Applicant could consider phrasing the limitation as product by process language, as in claim 4.
Claim 3 recites the limitation “silica having -Si-OH groups” in line 5 and also recites "the Si-OH groups of the silica form a -Si-O-Si- bond with the -Si-O3- group of the functionalized triblock" in line 8. This language renders the claim internally contradictory because, as it is currently worded, the claim requires two states for the pendant oxygens of the silica; however, an atom cannot simultaneously be in the form of a free hydroxyl and also bound by two covalent bonds to separate silicon atoms, as depicted in the claim. To overcome the rejection, Applicant could consider phrasing the limitation as product by process language, as in claim 4.
Claims depending from rejected claims have also been rejected because they incorporate all of the limitations of the claims from which they depend, but fail to resolve the indefiniteness concerns outlined above.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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, 2, 5, 8, 10, and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Hubbell et al. (US 5,410,016; issue date: 04/25/1995) in view of Wang et al. (Soft Matter vol 8, page 6048; publication year: 2012) and Mazzocchetti et al. (Biomacromolecules Vol 8, pages 672-678; publication year: 2007; cited in the IDS filed 04/03/2023).
With respect to claim 1, Hubbell discloses biodegradable hydrogels formed from a network of crosslinked polymers that function as controlled release carriers (abstract, title). In a preferred embodiment, a hydrogel begins with a biodegradable, polymerizable, macromer including a core, an extension on each end of the core, and an end cap on each extension. The core is a hydrophilic polymer or oligomer; each extension is a biodegradable polymer or oligomer; and each end cap is an oligomer, dimer or monomer capable of cross-linking the macromers (col 8, lines 5-12). Hubbell discloses that choice of hydrogel macromers [i.e. the building blocks used to form the polymer] can produce a wide range of permeability, pore sizes, and degradation rates for a variety of applications in surgery, diagnosis, and treatment (col 1, lines 30-34) and that time required for a polymer to degrade [in vivo] can be tailored by selecting appropriate monomers (col 3, lines 11-14). The macromers include a water soluble region and one region which is biodegradable (col 4, lines 33-35). The water soluble region is preferably PEG (col 5, lines 20-21, col 8, lines 40-41, and examples) and the biodegradable region is preferably selected from inter alia a lactide (col 8, lines 50-55, and e.g. example 1 col 11-16). The hydrogel has benefits for active agent delivery including reducing deactivation of the entrapped material (i.e. the active agent) and reducing catastrophic burst effects (col 5, lines 54-56). Hubbell discloses that the hydrogel is polymerized (including crosslinking) by free-radicle polymerization for example by photosensitive chemicals and dyes (col 4, lines 30-35). The method of synthesizing the hydrogel requires the steps of exposing the macromers, a biologically active substance, and a light-sensitive free-radicle polymerization initiator to light (see e.g. col 9, lines 7-8 and col 10, lines 20-27).
Thus, Hubbell discloses a hydrogel formed from crosslinked polymer chains having PEG and lactic acid groups; which embraces the following segment of formula (1) recited in instant claim 1:
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Hubbell does not disclose crosslinking the PLA-PEG-PLA via a (3-isocyanatopropyl)triethoxysilane moiety to a silica particle, as required by the instant claims.
Wang, in the analogous art of biomedical applications for hydrogels, discloses that crosslinking polymer hydrogels increases the mechanical strength of hydrogels (title, page 6048). Wang discloses further that while polymer hydrogels resemble biological hydrogels in some respects, most synthesized hydrogels are soft, weak, and brittle, limiting them in clinical application (page 6048, left col). Wang reports that crosslinking via covalently bound silica particles resulted in significant improvement in hydrogel toughness (abstract).
Mazzocchetti, in the analogous art of PLA-PEG-PLA crosslinked polymers in biomedicine, discloses an organic-inorganic hybrid of covalently interconnected nanocomposites formed from the following polymer covalently bound to silica at the Si-O- termini (Scheme 1, page 674):
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Thus in view of Wang one would have understood that crosslinking hydrogels with silica particle provides structure that more closely resembles naturally occurring biological hydrogels and would have understood in view of Mazzocchetti that PLA-PEG-PLA units could be crosslinked by silica particles when the PLA-PEG-PLA moiety has an end group capable of binding silica, such as (3-isocyanatopropyl)triethoxysilane (ICPTES) via a urethane linkage between the ICPTES and the terminus of the PLA block.
It would have been prima facie obvious to use the crosslinked polymer disclosed by Mazzocchetti as the hydrogel polymer in Hubbell’s invention. The skilled artisan would have been motivated to do so in order to increase the mechanical strength of the gel for applications where a firmer gel was suitable (e.g. collagen replacement). The artisan of ordinary skill would have had reasonable expectation of success because crosslinked PLA-PEG-PLA block copolymers were known to form hydrogels, forming a hydrogel would merely require adding an aqueous solvent to the composite disclosed by Mazzocchetti, and because Mazzocchetti provides the synthetic route to generate the particular organic-inorganic composite disclosed therein and recited in the instant claims.
With regard to the values for m and n recited in the instant claims, as noted above, the amount of PEG (hydrophilic monomer) and the amount of PLA (biodegradable monomer) can be used to control the water solubility/absorption and the rate of degradation of the hydrogel, therefore the examiner considers optimizing these parameters to be a matter of routine for the artisan of ordinary skill (see MPEP 2144.05).
With regard to the percentage of triblock molecule, silica, and water required by the instant claims, the relative proportions of silica and triblock copolymer and water would determine the mechanical properties of the gel, and the examiner considers it well within the skill of the ordinary artisan to optimize the amounts of each component of the hydrogel to arrive at a composition having rigidity/flowability etc. suited to any particular purpose in biomedicine.
With regard to claim 2, the examiner considers the properties recited in instant claim 2 to be inherent features of forming a hydrogel with the network disclosed by Mazzocchetti because the hydrogel forming composite of the instant claims is identical to the substance disclosed by Mazzocchetti.
With regard to claim 5, the silica in Mazzocchetti’s composite network is formed from the alkoxysilane TEOS tetraethoxy silane (see: Experimental Section, page 673).
With regard to claims 8, 10, and 11, Hubbell discloses that the hydrogels are used to deliver bioactive agents (i.e. therapeutically active agents; col 10, lines 20-37).
Claims 3, 4, 6, 7, 9, and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Hubbell et al. (US 5,410,016; issue date: 04/25/1995), Wang et al. (Soft Matter vol 8, page 6048; publication year: 2012), and Mazzocchetti et al. (Biomacromolecules Vol 8, pages 672-678; publication year: 2007; cited in the IDS filed 04/03/2023) as applied to claims 1, 2, 5, 7, 8, 10, and 11 above, and further in view of Zugates et al. (WO2019/195546; publication date 10/10/2019; effectively filed date 04/04/2018, with priority to US provisional application no. 62652548).
With regard to claims 3, 4, and 16, the relevant disclosures of Hubbell, Wang, and Mazzocchetti are set forth above. None of these references disclose a second hydrogel material in the form of particles dispersed evenly throughout the first hydrogel and the first hydrogel having greater water content than the second hydrogel.
Zugates discloses that hydrogels for delivery of therapeutic agents (abstract) can be broken into particles (claim 42) and formulated within a gel (page 5, lines 20-24).
It would have been prima facie obvious to one of ordinary skill to distribute active agent containing particles formed from the hydrogel of Hubbell/Wang/Mazzocchetti within a continuous phase of the same hydrogel, having different amounts of water. The artisan of ordinary skill would have recognized this arrangement as suitable for drug delivery (see MPEP 2143(A): it is prima facie obvious to combine prior art elements according to known methods to yield predictable results).
With regard to the limitation that the second hydrogel particles be distributed homogeneously, this would have been routine practice for one of ordinary skill in the art. One would have been motivated to distribute active agent particles evenly in order to provide steady release of active agent and would have had reasonable expectation of success because this would merely require mixing until homogeneity was achieved.
The examiner notes that instant claim 4 recites product by process language; however, it was known in the art to break apart hydrogels in order to form them into particles, as established by Zugates.
With regard to claims 6 and 7, Hubbell discloses that the hydrogel is swollen with water (col 15, lines 3-11) and Zugates teaches that hydrogels for drug delivery may also contain water-miscible solvents such as ethanol based on the solubility of the gelators therein etc. (page 5, lines 3-25). It would have been obvious to include ethanol in the hydrogel of Hubbell/Wang/Mazzocchetti because one having ordinary skill would have recognized ethanol as a suitable co-solvent in this system. With regard to the relative proportions of water and ethanol required by instant claim 7, it would have been routine for one of ordinary skill to optimize the solubility of the active agents and gel formers by adjusting the amount of co-solvent present in the formulation.
With regard to claim 9, as explained above, it would have been obvious to use the hydrogel of Hubbell/Wang/Mazzocchetti/Zugates to deliver a therapeutically active agent because such was the purpose of Hubbell and Zugates.
Response to Arguments
Applicant's arguments filed 04/29/2026 have been fully considered but they are not persuasive.
On pages 7-8, Applicant argues that the structure disclosed by Hubbell is incapable of reacting with an isocyanate because it lacks free hydroxyls.
This is not persuasive because the structure cited by Applicant is simply the repeating monomer structure without the end groups that are necessarily present on any polymer, as recited in instant claim 1. In this case, the polymer formed from lactic acid monomers disclosed by Hubbell would necessarily have pendant hydroxyls at each one, and anyone of ordinary skill, i.e. an individual with a Ph.D. in polymer chemistry, would have understood this.
On page 8, Applicant argues that Mazzocchetti does not disclose the claimed urethane linkage but rather a linkage between the carbon atom which is bonded directly to one oxygen atom with a single bond, and one with a double bond is not bound directly to a nitrogen atom but rather there is an additional carbon atom between the carbon and the nitrogen.
This argument is not persuasive because although Mazzocchetti does disclose the structure replicated by Applicant on page 8 of the remarks (page 674, left column), the disclosure is not limited to only this linkage. On page 674, right col, Mazzocchetti also discloses the claimed urethane linkage at the top of the page.
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On page 9, Applicant argues that Zugates disclosure of administering hydrogel particles “in a gel” is insufficient to render obvious the administering them in the same gel.
The examiner respectfully disagrees. The gel of Hubbell/Wang/Mazzocchetti would have been obvious to the artisan of ordinary skill as set forth in the rejection and therefore one having ordinary skill would also have recognized it as a suitable vehicle to deliver a subset of particles formed from the same gel.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KATHERINE PEEBLES whose telephone number is (571)272-6247. The examiner can normally be reached Monday through Friday: 9 am to 3 pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ali Soroush can be reached at (571)272-9925. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KATHERINE PEEBLES/ Primary Examiner, Art Unit 1617
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