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 .
Response to Arguments
Applicants' arguments, filed August 19, 2025, have been fully considered but they are not deemed to be fully persuasive. The following rejections and/or objections constitute the complete set presently being applied to the instant application.
Applicants argue that the previous rejections do not teach the fluorinated polyethylene glycol (PEG) polymer formed by combining a PEG polymer, cysteine ethyl ester and a fluorinating agent as now recited in claim 1.
In view of the amendments to claim 1, a new ground of rejection is set forth below. Claim 1 as currently amended is a product by process claim wherein the claimed process results in a particular structure of the linker portion of the resultant structure, as can be readily seen in Figure 1 of the instant application.
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, 5, 13 and 33 are rejected under 35 U.S.C. 103 as being obvious over Kabanov et al. (US 6,316,505) in view of Liu et al. (ChemComm, published March 20, 2019).
Kabanov et al. discloses block copolymers containing a fluorinated hydrocarbon unit, a hydrocarbon unit and poly(oxyethylene) unit in fluid formulations with pharmaceutical agents (whole document, e.g., abstract). Depending on the which of R1 and R2 is the fluorinated block in formulas IA, II1, IIIA, IB, IIB and IIIB, the behavior of the micelles varies (col 4, ln 15 – 35). A fluorinated monovalent R1 and divalent hydrocarbon R2 produce very stable micellar form of drugs that do not interact with non-target tissues in the body making them useful as micelle microcontainers for drug with decreased drug metabolism and liver uptake (col 4, ln 15 – 26). A monovalent hydrocarbon R1 and fluorinated divalent hydrocarbon R2 results in activity in MDR cells (col 4, ln 27 – 30) and using a mixture of the two produces formulations which provide both micelle-mediated drug delivery and anti-MDR activity and related activity associated with surfactant interactions with cell membranes (col 4, ln 31 – 36). The linking groups generally do not contribute to the utility of the compounds but serve to covalently join the blocks of the copolymer chain and can be a wide variety of divalent groups (col 4, ln 37 – 41). Linking can be accomplished by a number of reactions, many of which have been described generally in conjugate chemistry using various terminal groups that either react or are replaced (col 4, ln 42 onward). Various suitable starting materials bearing various groups are disclosed starting at col 6, ln 45. Fluorine containing materials disclosed include heptafluorobutyric acid and the anhydride and chloride derivatives thereof; nonafluoropentanoic acid (also known as nonafluorovaleric acid) and pentafluoropropionic acid (col 6, ln 49 – 51). The hydrophilic homopolymer can be polyethylene oxides (col 7, ln 60 – 61) and a large number of mono- and di-functional PEG starting materials are available including PEG with a molecular weight (mw) of 1,000 (1K) or 5,000 (5K; col 8, ln 8 – 13). Example 15 (col 22, ln 11 onward) reports the formation of micelles when determining the critical micelle concentration (CMC) for some of the materials made. Structures such as those in the abstract and at col 22, ln 54 – 57 contain no ionizable groups so the micelles would be neutral. Based on the list of possible pharmaceuticals with which the disclosed block copolymers can be an agent, therapeutic agents can be present in the micelles formed from the block copolymers (col 8, ln 47 onward). The prior art need not explicitly disclose that the micelles are capable of delivering the therapeutic agent to mitochondria independent of potential in order to render the claims obvious as there is no evidence of record that these fluorine containing micelles would not deliver the therapeutic agent to mitochondria independent of potential
The presence of a linker constructed using a reaction involving cysteine ethyl ester is not disclosed.
Liu et al. discloses the preparation of targeted conjugates of the drug bortezomib (BTZ) that is pH sensitive (whole document, e.g., abstract). FA, folic acid, was used as a targeting moiety to prepare BTZ conjugates for cancer-specific drug delivery and therapy (p 4254, col 2, ¶ 1). The conjugates were prepared using a facile method which for the PEG containing construct FA-PEG-Cat-BTZ, with Cat being a catechol linker to the FA portion, is shown in Figure S1 and section 1.2.3 of the Supplemental Information. As can be seen in Figure S1, PEG bearing a maleimide group (top line) is reacted with the targeting agent (FA) and cysteine ethyl ester reacted with FA to form FA-Cys (second line) that each of those products in a 1:1 molar ratio were reacted to prepare the conjugate shown in line 3, that was then reacted with BTX to form the final conjugate.
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to use the pH sensitive linker involving a cysteine ethyl ester taught bt Liu et al. to prepare the conjugates of Kabanov et al. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because Kabanov et al. discloses that various conjugation strategies are known in the art and can be used to prepare the co-polymers disclosed therein. A pH sensitive linker such as that disclosed by Liu et al. offers the potential for alterations to the copolymer structure in response to changes in pH. Various fluorine containing compounds and mono- or di-functional PEGs are disclosed by Kabanov et al. and are known to those of ordinary skill in the art. Such an artisan can select the appropriate reactants to carry out the desired conjugation using the reactions of Liu et al. to produce a pH sensitive linker to product a construct having a structure as required by the process used to prepare the claimed construct.
As to new claim 33, PEG polymers of various molecular weights are known to those of ordinary skill in the art who can select from those that are available with known molecular weights. There is no evidence of record as to the criticality of the molecular weight of the PEG portion of the claimed polymers.
Conclusion
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 Nissa M Westerberg whose telephone number is (571)270-3532. The examiner can normally be reached M - F 8 am - 4 pm.
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/Nissa M Westerberg/Primary Examiner, Art Unit 1618