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 .
Formal Matters
Applicant’s arguments in the reply filed on 23 October 2025 are acknowledged and have been fully considered. Claims 1-20 are pending. Claims 1-2 are under consideration in the instant office action. Claims 3-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and/or species, there being no allowable generic or linking claims. Claims 21-23 are canceled. Applicant’s arguments did not overcome the rejections set forth under 35 USC 103 in the previous office action for reasons set forth in the previous office action and herein below.
Rejections Maintained
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 1-2 remain rejected under 35 U.S.C. 103 as being unpatentable over Lee et al. (Biomacromolecules 2002, 3, 1038-1047) in view of Messersmith et al. (US20030087338, previously provided).
Applicants’ claims
Applicants claim a compound of formula I:
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Elected Species: Applicant elected the compound of Formula I where:
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Species Expansion for search and examination: The examiner expanded for search and examination purposes wherein R3 and R4 are hydrogen.
Determination of the Scope and Content of the Prior Art
(MPEP 2141.01)
Lee et al. teach 3,4-Dihydroxyphenylalanine (DOPA) residues are known for their ability to impart adhesive and curing properties to mussel adhesive proteins. In this paper, we report the preparation of linear and branched DOPA- modified poly(ethylene glycol)s (PEG-DOPAs) containing one to four DOPA endgroups. Gel permeation chromatography-multiple-angle laser light scattering analysis of methoxy-PEG-DOPA in the presence of oxidizing reagents (sodium periodate, horseradish peroxidase, and mushroom tyrosinase) revealed the formation of oligomers of methoxy-PEG-DOPA, presumably resulting from oxidative polymerization of DOPA endgroups. In the case of PEG-DOPAs containing two or more DOPA endgroups, oxidative polymerization resulted in polymer network formation and rapid gelation. The amount of time required for gelation of aqueous PEG-DOPA solutions was found to be as little as 1 min and was dependent on the polymer architecture as well as the type and concentration of oxidizing reagent used. Analysis of reaction mixtures by UV-vis spectroscopy allowed the identification of reaction intermediates and the elucidation of reaction pathways. On the basis of the observed reaction intermediates, oxidation of the catechol side chain of DOPA resulted in the formation of highly reactive DOPA-quinone, which further reacted to form cross-linked products via one of several pathways, depending on the presence or absence of N-terminal protecting groups on the PEG-DOPA. N-Boc protected PEG-DOPA cross-linked via phenol coupling and quinone methide tanning pathways, whereas PEG-DOPA containing a free amino group cross-linked via a pathway that resembled melanogenesis. Similar differences were observed for the rate of gel formation as well as the molecular weight between cross-links (Mc), calculated using equilibrium swelling and the Flory-Rehner equation (see abstract). Lee et al. teach on page 1043 various ways of conjugating the polymer PEG to L-DOPA as follows:
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The examiner for instance notice that the following structure meets the claimed compound:
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Ascertainment of the Difference Between Scope of the Prior Art and the Claims
(MPEP 2141.02)
Lee et al. do not specifically teach PEG2000. This deficiency is cured by the teachings of Messersmith et al.
Messersmith et al. teach 3,4-Dihydroxyphenyl-L-alanine (DOPA) is an unusual amino acid found in mussel adhesive proteins (MAPs) that form tenacious bonds to various substrates under water. DOPA is believed to be responsible for the adhesive characteristics of MAPs. This invention relates to a route for the conjugation of DOPA moieties to various polymeric systems, including but not limited to poly(ethylene glycol) or poly(alkylene oxide) systems such as poly(ethylene oxide)-poly(propylene oxide)-poly(ethy lene oxide) (PEO-PPO-PEO) block copolymers (abstract). The present invention provides novel polymeric compositions through incorporation of one or more DOPA moieties - DOPA-containing or catecholic moieties and/or DOPA/catecholic-like moieties or components. Such compositions are available as described, below, and/or through a general synthetic procedure for polymer end-group activation. With respect to the latter, various polymers or monomeric component thereof can preferably be activated using carbonate chemistry. In particular, a succinimidyl carbonate-activated polymeric component reacted with DOPA or a DOPA-derivative can provide a stable urethane conjugate. Illustrating several preferred embodiments, two possible pathways (a) and (b) in Scheme 1, below, show coupling with a poly(alkylene oxide) in either aqueous or non-aqueous solvents, without compromising desired bioadhesion. Oscillating rheometry and differential scanning calorimetry show that, depending upon the polymeric component, such DOPA-modified polymers have the ability to form polymer hydrogels by a thermally triggered self-assembly process. With respect to various other preferred embodiments, DOPA-containing or such structurally -related polymers can be adsorbed from solution or liquid media for purposes of surface modification and/or particulate stabilization. This part, the present invention is a biomimetic adhesive composition, including 1) a polymeric component providing or having a surface active effect such as described herein, and 2) at least one catecholic component coupled to the polymeric component. Various polymeric components providing surface active effect will be well-known to those skilled in the art made aware of this invention, such surface activity as can relate to reduced particulate agglomeration and anti-biofouling. For instance, the polymeric component can be water soluble, depending upon end use application, and/or capable of micelle formation depending upon various other end use applications. Preferably, the polymeric component is poly(ethylene oxide)(PEO) or poly(ethylene glycol)(PEG), depending upon monomeric starting material and subsequent polymerization, and can further include one or more hydrophobic components, as described below (paragraph 0089). Regardless, the catecholic component of the present invention is preferably a DOPA precursor, structure, moiety and/or residue conjugated to the polymeric component, such a precursor, residue or moiety as can be incorporated into a peptide or oligopeptide component conjugated with the polymeric component. Such a residue can be derivatized, as would be understood by those skilled in the art, such derivitization limited only by the compositional retention of some adhesive characteristic. Likewise, the catecholic moiety of such a component can be structurally modified or functionally protected insofar as adhesive characteristics are retained or available with subsequent synthetic manipulation. The catecholic component can be coupled to the polymeric component through a variety of synthetic procedures as would be understood by those skilled in the art or as otherwise described herein, depending upon end group functionality. For instance, a DOPA residue can be coupled to a polymeric component to provide the desired conjugate composition, through either urethane or amide bond formation (paragraph 0091). More particularly, if coupled to the polymeric component via urethane bond formation, the carboxylic acid group of the DOPA component can be esterified or derivatized with various other functional groups. Alternatively, the DOPA component can be coupled to a polymeric component (e.g., amidation or esterification depending on polymer end group, —NH 2 or —OH) providing a DOPA functionality which can be derivatized by any of numerous known protecting groups, including without limitation the boc protecting group. Conversely, N-group protection of a DOPA component can leave the carboxylic acid group available for multi-functional derivatization and/or a higher density of polymeric components conjugated therewith. Retention of catecholic functionality and/or a related dihydroxy structural relationship can be illustrated using a dopamine component, whereby conjugation with a suitable polymeric component can be achieved with one of the several coupling strategies described herein. The use of PEG2000 is demonstrated in examples 12a and 16b while coupling DOPA to PEG. Messersmith et al. teach it can also be an object of the present invention to provide one or more adhesive polymeric systems which can be tailored by way of composition, molecular weight and/or concentration to provide desired gelation properties(paragraph 0086).
Finding of Prima Facie Obviousness Rational and Motivation
(MPEP 2142-2143)
It would have been prima facie obvious to a person of ordinary skill before the effective filing date of the instant invention to modify the teachings of Lee et al. by utilizing PEG2000 because Messersmith et al. teach 3,4-Dihydroxyphenyl-L-alanine (DOPA) is an unusual amino acid found in mussel adhesive proteins (MAPs) that form tenacious bonds to various substrates under water. DOPA is believed to be responsible for the adhesive characteristics of MAPs. This invention relates to a route for the conjugation of DOPA moieties to various polymeric systems, including but not limited to poly(ethylene glycol) or poly(alkylene oxide) systems such as poly(ethylene oxide)-poly(propylene oxide)-poly(ethy lene oxide) (PEO-PPO-PEO) block copolymers (abstract). The present invention provides novel polymeric compositions through incorporation of one or more DOPA moieties - DOPA-containing or catecholic moieties and/or DOPA/catecholic-like moieties or components. Such compositions are available as described, below, and/or through a general synthetic procedure for polymer end-group activation. With respect to the latter, various polymers or monomeric component thereof can preferably be activated using carbonate chemistry. In particular, a succinimidyl carbonate-activated polymeric component reacted with DOPA or a DOPA-derivative can provide a stable urethane conjugate. Illustrating several preferred embodiments, two possible pathways (a) and (b) in Scheme 1, below, show coupling with a poly(alkylene oxide) in either aqueous or non-aqueous solvents, without compromising desired bioadhesion. Oscillating rheometry and differential scanning calorimetry show that, depending upon the polymeric component, such DOPA-modified polymers have the ability to form polymer hydrogels by a thermally triggered self-assembly process. With respect to various other preferred embodiments, DOPA-containing or such structurally -related polymers can be adsorbed from solution or liquid media for purposes of surface modification and/or particulate stabilization. This part, the present invention is a biomimetic adhesive composition, including 1) a polymeric component providing or having a surface active effect such as described herein, and 2) at least one catecholic component coupled to the polymeric component. Various polymeric components providing surface active effect will be well-known to those skilled in the art made aware of this invention, such surface activity as can relate to reduced particulate agglomeration and anti-biofouling. For instance, the polymeric component can be water soluble, depending upon end use application, and/or capable of micelle formation depending upon various other end use applications. Preferably, the polymeric component is poly(ethylene oxide)(PEO) or poly(ethylene glycol)(PEG), depending upon monomeric starting material and subsequent polymerization, and can further include one or more hydrophobic components, as described below (paragraph 0089). Regardless, the catecholic component of the present invention is preferably a DOPA precursor, structure, moiety and/or residue conjugated to the polymeric component, such a precursor, residue or moiety as can be incorporated into a peptide or oligopeptide component conjugated with the polymeric component. Such a residue can be derivatized, as would be understood by those skilled in the art, such derivitization limited only by the compositional retention of some adhesive characteristic. Likewise, the catecholic moiety of such a component can be structurally modified or functionally protected insofar as adhesive characteristics are retained or available with subsequent synthetic manipulation. The catecholic component can be coupled to the polymeric component through a variety of synthetic procedures as would be understood by those skilled in the art or as otherwise described herein, depending upon end group functionality. For instance, a DOPA residue can be coupled to a polymeric component to provide the desired conjugate composition, through either urethane or amide bond formation (paragraph 0091). More particularly, if coupled to the polymeric component via urethane bond formation, the carboxylic acid group of the DOPA component can be esterified or derivatized with various other functional groups. Alternatively, the DOPA component can be coupled to a polymeric component (e.g., amidation or esterification depending on polymer end group, —NH 2 or —OH) providing a DOPA functionality which can be derivatized by any of numerous known protecting groups, including without limitation the boc protecting group. Conversely, N-group protection of a DOPA component can leave the carboxylic acid group available for multi-functional derivatization and/or a higher density of polymeric components conjugated therewith. Retention of catecholic functionality and/or a related dihydroxy structural relationship can be illustrated using a dopamine component, whereby conjugation with a suitable polymeric component can be achieved with one of the several coupling strategies described herein. One of ordinary skill in the art would have been motivated to do so because Messersmith et al. first the use of PEG2000 in examples 12a and 16b while coupling DOPA to PEG. Furthermore, Messersmith et al. teach that it can also be an object of the present invention to provide one or more adhesive polymeric systems which can be tailored by way of composition, molecular weight and/or concentration to provide desired gelation properties(paragraph 0086). The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945) (Claims to a printing ink comprising a solvent having the vapor pressure characteristics of butyl carbitol so that the ink would not dry at room temperature but would dry quickly upon heating were held invalid over a reference teaching a printing ink made with a different solvent that was nonvolatile at room temperature but highly volatile when heated in view of an article which taught the desired boiling point and vapor pressure characteristics of a solvent for printing inks and a catalog teaching the boiling point and vapor pressure characteristics of butyl carbitol. "Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." 325 U.S. at 335, 65 USPQ at 301.).
A person of ordinary skill in the art would have had a reasonable expectation of success in combining the teachings of Lee et al and Messersmith et al. because both references teach PEG coupled L-DOPA. Furthermore, in the case where the claimed molecular weights "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). Furthermore, differences in concentration or molecular weight will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. "[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).
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. 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 instant invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed on 23 October 2025 have been fully considered but they are not persuasive.
Applicant argues the Examiner's reading of Lee's structure above is incorrect because the α,ß-Dehydro DOPA has a α,ß-carbon-carbon double bond which is the site of step D, cross-linking polymerization. The claimed compounds of formula I have the following structure:
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The claimed compounds have no α,B-carbon-carbon double bond, or any cross-linking at the a,ß- carbon-carbon bond:
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Thus, the claimed compounds and those disclosed in Lee have very significant differences in chemical structure. This deficiency in the disclosure of Lee cannot be cured by Messersmith. Moreover, as is well known, there is a high degree of unpredictability in the chemical arts, especially as it relates to structure of small molecules and impact of change in structure on activity. Indeed, the compounds disclosed in Lee and Messersmith are concerned with adhesive and gelation properties, and formation of hydrogels (see conclusions, page 1047 of Lee and paragraph 0007 of Messersmith). In contrast, the presently claimed compounds are intended to be used for the treatment of Parkinson's disease. Therefore, claims 1 and 2 are not obvious over Lee in view of Messersmith. Accordingly, the Applicant requests that this rejection be withdrawn.
The above assertions are not found persuasive because Lee et al. is starting from an exactly the same compound that reads on the claimed structure except the fact that the examiner expanded the search wherein R3 and R4 are hydrogen. There is no presence of a double bond in the structure. See Applicant’s structure in comparision with the starting compound in Lee et al.
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Applicant is picking an intermediate compound to make an argument which is not applicable. R3 and R4 in the current application are hydrogen in Lee et al. The polymer can be attached to R2 in Lee et al. structure.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. 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 TIGABU KASSA whose telephone number is (571)270-5867. The examiner can normally be reached on 8 AM-5 PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, David Blanchard can be reached on 571-272-0827. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/TIGABU KASSA/Primary Examiner, Art Unit 1619