DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicants’ submission filed on November 25 2025 has been entered.
Receipt of Arguments/Remarks filed on November 25 2025 is acknowledged. Claims 4-9, 13, 15-24, 30-47 and 49-75 were/stand cancelled. Claim 1 was amended. Claims 1-3, 10-12, 14, 25-29 and 48 are pending. Claims 25-29 and 48 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on December 2 2024. Claims 1-3, 10-12 and 14 are directed to the elected invention.
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 .
Claim Rejections - 35 USC § 112-Indefiniteness
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, 10-12 and 14 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 as currently written is vague and indefinite. The claim recites “the polymer being a member of a polymeric network of associated polymers permeable to a micrococcal nuclease of S. aureus”. While the specification teaches the oligonucleotide is linked at the first end to a polymeric network (paragraph 0015) and a hydrogel network (paragraph 00118), the specification does not indicate what polymers specifically are permeable to a micrococcal nuclease. The examiner can find no evidence that this is a known class of polymers. Therefore, it isn’t clear if the limitation is merely encompassing hydrogels, as taught in the specification, or if there is some other feature of the network that allows the network to be permeable to a micrococcal nuclease. The specification fails to indicate what specific polymers or what specific structure of polymers allows for the claimed function.
Claims 10-12 depend from claim 1. Claim 1 recites the oligonucleotide comprises a sequence selected from a particular group which include 2’-O-methylation and/or phosphorothioate modification. Claim 10 recites the oligonucleotide comprises one or more chemically modified pyridines and purines. Claim 11 however recites “the one or more chemical modifications” which has to be referring to the one or more chemically modified pyrimidines and purines in claim 10 but recites 2’-O-carboxymethyl or 2’-fluoro modifications. However, these modifications do not occur on the pyrimidine or purine but instead on the sugar of the nucleoside. Claim 12 recites the one or more chemical modifications comprise one or more phosphorothioate modifications. However, claim 1 already recites phosphorothioate modifications. Additionally, the “one or more chemical modifications” has to be referring back to the modifications on the pyrimidines and purines in claim 10 but the phosphorothioate modification does not occur on the pyrimidine or purine. This creates confusion to the scope of the oligonucleotides claimed. Claims 11 and 12 suggest the modifications do not occur on the pyrimidine or purine, which is what is required in claim 10. Therefore, what is the scope of chemical modifications encompassed. Additionally, these claims depend from claim 1 which already recites chemical modifications and these claims do not make it clear they are in addition to the chemical modifications already recited.
Claims 2-3 and 14 are included in the rejection as they depend on a rejected base claim and they do not clarify the issues.
Claim Rejections - 35 USC § 112-New Matter
The following is a quotation of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), first paragraph:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-3, 10-12 and 14 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
Claim 1 introduces new matter as the claims recite the limitation: "the polymer being a member of a polymer network of associated polymers permeable to a micrococcal nuclease of S. aureus”. There is no support in the specification for this limitation. The limitation of: what constitutes a polymer being a member of a polymeric network of associated polymers permeable to a micrococcal nuclease of S. aureus was not described in the specification as filed, and person skilled in the art would not recognize in the applicant’s disclosure a description of the invention as presently claimed. The specification discloses an oligonucleotide is linked at the first end to a polymeric network (paragraph 0015) and a hydrogel network (paragraph 00118) but does not describe the instantly claimed limitation. The instant specification fails to describe this limitation or indicate what polymers/structure meets this required and from MPEP 2163.06: “Applicant should therefore specifically point out the support for any amendments made to the disclosure.” Applicant has not directed the Examiner to the support in the specification for the amendments. Therefore, it is the Examiner’s position that the disclosure does not reasonably convey that the inventor had possession of the subject matter of the amendment at the time of filing 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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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, 10 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Bossard et al. (USPGPUB No. 20060239960, cited in the Office Action mailed on 3/18/25) in view of Hernandez et al. (Chem Commun, 2014, cited on PTO Form 1449) and Greenwald et al. (USPGPUB No. 20040142858, cited in the Office Action mailed on 3/18/25).
Applicant Claims
The instant application claims a polymer-drug conjugate comprising an oligonucleotide of about 6 to about 30 nucleotides in length having a first end and a second end, wherein the oligonucleotide is linked at the first end to a polymer, the polymer being a member of a polymeric network of associated polymers permeable to a micrococcal nuclease of S. aureus, and at the second end to an antimicrobial agent wherein:
the oligonucleotide comprises a sequence selected from the group consisting of mC-mG-T-T-mC-mG, C*-G*-T-T-C*-G*, mC*-mG*-T-T-mC*-mG*, mCmG*-T-T- mC*-mG, mC*-mG-T-T-mC-mG*, and mC-mU-mC-mG-T-T-mC-mU-mC-mG (SEQ ID NO: 1), wherein m denotes 2'-O-methylation while * denotes phosphorothioate modification; the oligonucleotide is configured to be cleaved by the micrococcal nuclease of S.aureus, causing release of a cleavage product comprising the antimicrobial agent and a cleaved portion of the oligonucleotide including the second end, from the polymer, the released cleavage product retaining antimicrobial activity; and the polymer network is configured to allow diffusion of the released antimicrobial agent out of the polymeric network, wherein the antimicrobial agent is selected from the group consisting of vancomycin, gentamicin, tobramycin, a cephalosporin, and a quinolone.
While the polymer network is indefinite for the reasons set forth above, in light of the teachings of the specification, this network is interpreted as a hydrogel for the purposes of art.
Claim 10 is interpreted as not requiring a modification on the purine or pyrimidine specifically but anywhere on the nucleotide (i.e. linkage or sugar modifications are included).
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Bossard et al. is directed to polymer-based compositions and conjugates of antimicrobial agents. Claimed is a conjugate comprising a residue of an antimicrobial agent attached to a water soluble polymer by a degradable linker (claim 1). It is taught that some have suggested the use of PEGylation technology, or the attachment of a poly(ethylene glycol) derivative to a protein in order to prolong the antimicrobial agents in vivo half-life (paragraph 0006). Degradable linkers include oligonucleotides (paragraph 0075). Taught are the use of spacers (paragraphs 0123, 0126 and 0157). It is taught that the polymer can form a hydrogel which is a three-dimensional network (paragraph 0085; 0090; 0118; 0121). It is taught that the polymer portion of the conjugate falls off in the body to release the native antimicrobial agent (i.e. the antimicrobial agent retains activity) (paragraph 0090).
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Bossard et al. suggests conjugation of an antimicrobial agent to a polymer via degradable oligonucleotide, Bossard et al. does not expressly provide motivation for selecting an oligonucleotide. However, this deficiency is cured by Hernandez et al. and Greenwald et al.
Hernandez et al. is directed to nanokeepers which are stimuli responsive nanocapsules for programmed specific targeting and drug delivery. Taught is the use of nanokeepers a therapeutic option based on the nuclease activity of MN (micrococcal nuclease) as a stimulus-response for specific targeting and controlled release (page 9489, last full paragraph). S. aureus is a major cause of human disease, responsible for several conditions and has emerged as a major public health threat. Taught is using the secreted nuclease, MN, of S. aureus as a trigger mechanism. An oligonucleotide probe sequence (11mer) that has two central thymidines (TT) flanked by 2’-O-methyl nucleotides (mCmUmCmGTTmCmGmUmUmC). This probe confers specificity to MN while resistance to endogenous nuclease in mouse and human serum (page 9490, left column). Taught is the use of nanokeepers with vancomycin which is a common antibiotic for treating S. aureus which are designed to release only by specific actuation of MN (page 9491, left column). The TT is where the cleavage occurs and that the TT location can be changed (page 9490, right column; page 9491, left column, second full paragraph).
Greenwald et al. is directed to prodrugs of vancomycin with hydrolysis resistant polymer linkages. Prodrugs of vancomycin have been proposed as a way of increasing the solubility and circulating life of the drug (paragraph 0003). Prodrugs include chemical derivatives of a biologically active parent compound which, upon administration, will eventually liberate the active parent compound in vivo. The rate of release of the active drug is influenced by several factors including the rate of hydrolysis of the linker which joins the parent biologically active compound to the prodrug carrier (paragraph 0004).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Bossard et al., Hernandez et al. and Greenwald et al. and utilize the oligonucleotide of Hernandez et al. as the linker between the polymer and an antimicrobial such as vancomycin. One skilled in the art would have been motivated to utilize the oligonucleotide of Hernandez et al. to allow for MN triggered release of the vancomycin. As recognized by Bossard et al. and Greenwald et al. linkers between polymers and antimicrobials can be utilized to release a payload (i.e. the antimicrobial). Since vancomycin benefits from prodrug formation, i.e. linkage to a polymer, the oligonucleotide of Hernandez et al. would allow for release of the vancomycin only when the MN is present (i.e. the use of S. aureus as a trigger mechanism). Since Bossard et al. suggests that the linker can be an oligonucleotide; Greenwald et al. suggests that vancomycin can be conjugated to a polymer; and Hernandez et al. teaches the use of the oligonucleotide to provide for triggered release of vancomycin there is a reasonable expectation of success. Regarding the claimed cleavage product, attachment of the oligonucleotide of Hernandez et al. to both the polymer and vancomycin would result in cleavage of the vancomycin with a portion of the oligonucleotide attached (i.e. where the S. aureus cleaves) as Hernandez et al. teaches the TT is where cleavage occurs.
Regarding the claimed structure of the oligonucleotide, Hernandez et al. teaches mCmUmCmGTTmCmGmUmUmC which contains 11 nucleotides in length reading on claim 1 and 9 and which is a single strand. This sequence is taught as being susceptible to cleave by S. aureus which is a microbial nuclease. Hernandez et al. also teaches that the oligonucleotide is more stable against mammalian nucleases. The oligonucleotide taught in by Hernandez et al. contains one or more chemically modified pyrimidines and purines (i.e. 2’-O-methyl). This sequence comprises the mC-mG-T-T-mC-mG with 2’-O-methylation.
Regarding the claimed cleavage product retaining antimicrobial activity, Bossard et al. teaches the polymer conjugates themselves possess anywhere from about 0.1 to about 100% or more of the antimicrobial activity of the unmodified parent antimicrobial agent. It is taught that conjugates possessing little or no activity contain a hydrolyzable linkage connecting the polymer to the antimicrobial agent, so that regardless of the lack of activity in the conjugate, the active antimicrobial agent (or a derivative thereof) is released upon aqueous-induced cleavage of the hydrolyzable linkage. (paragraph 0136). This suggests the cleavage product contains activity.
Regarding the claimed polymer network and diffusion, Bossard et al. teaches the polymer can form a hydrogel reading on polymer network. Since the antimicrobial is designed to be released form the hydrogel, Bossard et al. teaches the same release as the instant specification diffusion (i.e. paragraph 00108 vancomycin diffuse out of the hydrogel).
Regarding claim 14, Bossard et al. suggests a spacer can be utilized. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Bossard et al., Hernandez et al. and Greenwald et al. and utilize a spacer in order to attach the linker and/or antimicrobial as suggested by Bossard et al. Furthermore, the spacer can be utilized to modify the degradability of the linker between the polymer and antimicrobial as suggested by Bossard et al.
Claims 3 and 11-12 are rejected under 35 U.S.C. 103 as being unpatentable over Bossard et al. in view of Hernandez et al. and Greenwald et al. as applied to claims 1-2, 10 and 14 above and in further view of Hernandez et al. (Nat. Med. 2014, cited on PTO Form 1449, cited in the Office action as Hernandez 2014).
Applicant Claims
The instant application claims the oligonucleotide is double stranded. The instant application claims the one or more chemical modifications comprise one or more 2’-O-carboxymethyl or 2’-fluoro modifications.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
The teachings of Bossard et al., Hernandez et al. and Greenwald et al. are set forth above.
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While 2’-O-methyl modifications are suggested, 2’-fluoro modifications are not taught. While a single strand oligonucleotide is taught, a double stranded is not expressly suggested. However, this deficiency is cured by Hernandez 2014.
Hernandez 2014 is directed to non-invasive imaging of staphylococcus aureus infections with a nuclease-activated probe. Hernandez 2014 sought a short oligonucleotide substrate that is both sensitive to MN and resistant to serum nucleases. Compared the MN- and serum nuclease-susceptibility of RNA oligomers composed of 2’-fluoro or 2’-O-methyl modified pyridines and unmodified purines with a DNA oligo, as DNA is the preferred substrate for MN among unmodified nucleic acids. The DNA probe was digested by MN more efficiently than either the 2’-fluoro or 2’-O-methyl modified pyridine RNA oligos but was, as expected, also substantially digested in serum. The 2’-fluoro and 2’-O-methyl modified pyridine RNA oligos were more stable in serum but less efficiently digested by MN (page 3).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Bossard et al., Hernandez et al., Greenwald et al. and Hernandez 2014 and utilize either single stranded RNA or double stranded DNA as the oligonucleotide. One skilled in the art would manipulate the type of oligonucleotide in order to achieve the desired degree of sensitivity. As taught by Hernandez 2014, DNA is the preferred substrate for MN but it is also digested in the serum. Therefore, one skilled in the art would recognize that DNA can be utilized when selectively is not critical but recognition by MN is important.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Bossard et al., Hernandez et al., Greenwald et al. and Hernandez 2014 and utilize 2’-fluoro modifications. One skilled in the art would have been motivated to utilize these modifications as Hernandez 2014 recognizes that these kinds of modifications can be included in oligonucleotide probes. This modification in combination with a TT sequence in the probe would be able to increase MN selectivity but reduce serum activity as suggested by Hernandez 2014.
One skilled in the art would have a reasonable expectation of success as both Hernandez et al. and Hernandez 2014 are concerned with designing probes which are sensitive to MN. Therefore, the use of an oligonucleotide to link an antimicrobial to a polymer allows for creation of a degradable linker that is triggered in the presence of nucleases. Since both Hernandez et al. and Hernandez 2014 suggests different modifications there is a reasonable expectation of success in using either single stranded or double stranded probes with a 2’-fluoro modification.
Claims 3 and 11-12 are rejected under 35 U.S.C. 103 as being unpatentable over Bossard et al. in view of Hernandez et al. and Greenwald et al. as applied to claims 1-2, 10 and 14 above and in further view of McNamara et al. (US Patent No. 20170224847, cited in the Office Action mailed on 3/18/25).
Applicant Claims
The instant application claims the oligonucleotide is double stranded. The instant application claims the one or more chemical modifications comprise one or more 2’-O-carboxymethyl or 2’-fluoro modifications. The instant application claims the one or more chemical modifications comprise one or more of phosphorothioate modifications.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
The teachings of Bossard et al., Hernandez et al. and Greenwald et al. are set forth above.
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Bossard et al. suggests an oligonucleotide linker, Bossard et al. is silent to whether the oligonucleotide is single and/or double stranded or chemically modified. However, this deficiency is cured by McNamara et al.
McNamara et al. is directed to oligonucleotide-based probes for detection of bacterial nucleases. Taught is a probe for detecting a microbial endonuclease comprising a substrate oligonucleotide of 2-30 nucleotides in length. The oligonucleotides contain one or more of 2’-O-methyl modifications or 2’-Fluoro modifications (paragraph 0012). In some embodiments the oligonucleotide comprises both RNA and DNA (i.e. fusion) (0014). Micrococcal nuclease (MN) is a robust extracellular nuclease produced by S. aureus. It readily digests DNA and RNA via endonuclease and exonuclease activities and its activity has been used to detect the presence of S.aureus in various contexts for decades (paragraph 0176). The nucleic acids of the invention in certain embodiments are single-stranded. In certain embodiments they are chimeric. They can include deoxyribonuclease resistant modifications such as a phosphorothioate deoxyribonucleotide (paragraph 0059). It is taught that linkers can be attached to the oligonucleotides (such as an ethylene glycol linker). The linker can be a phosphorothioate linkage (paragraph 0097). It is generally taught that nucleic acids include both single or double stranded form (paragraph 0038, 0078).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Bossard et al., Hernandez et al., Greenwald et al. and McNamara et al. and utilize either single-stranded or double-stranded or both oligonucleotides with phosphorothioate and/or 2’-fluoro and/or 2’-O-methyl modifications. One skilled in the art would have been motivated to manipulate the oligonucleotide based on the teachings of McNamara et al. Specifically, the use of a phosphorothioate linkage can be advantageous in linking the oligonucleotide to the polymer and/or the antimicrobial agent as McNamara et al. teaches this linkage can be used to attach the oligonucleotide to other moieties. McNamara et al. recognizes that MN readily digests both DNA and RNA. McNamara et al. teaches oligonucleotide probes can be either single stranded, double stranded or both. Finally, McNamara et al. recognizes various modifications such as 2’-fluoro which can be used to design oligonucleotide probes. Therefore, all of the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions and the combination would have yielded predictable results to one of ordinary skill in the art at the time of the invention. Note: MPEP 2143 KSR International Co. v. Teleflex Inc., 550 US 398, 82 USPQ 2d 1385 (2007). Since there is a desire to have an oligonucleotide linker which is susceptible to cleave in the presence of S. aureus in order to allow for release of an antimicrobial such as vancomycin when the bacteria is present, one skilled in the art would have been motivated to select the oligonucleotides of McNamara et al. for use as the degradable linker in Bossard et al. with a reasonable expectation of success.
Response to Arguments
Applicants’ arguments filed November 25 2025 have been fully considered but they are not persuasive.
Applicants argue that (1) the antimicrobial agents by Bossard et al. are peptides, unlike the antimicrobial agents of claim 1 as presently amended.
Regarding Applicants’ first argument, the examiner cannot agree. Vancomycin is a glycopeptide as shown in Greenwald et al. (see rejection above). Thus, they are peptide in nature which is what paragraph 0017 of Bossard et al. teaches. As taught by Bossard et al. teaches that to the extent the antimicrobial agent does not contain a carbonyl moiety, a carbonyl moiety can be introduced by providing glycosylated or glycated versions of the antimicrobial agent (paragraph 0142). Therefore, while Bossard et al. does not expressly teach vancomycin, the examiner cannot agree that the structure of this claimed antimicrobial is so different that one skilled in the art would not expect a reasonable expectation of success in its use.
Applicants argue that (2) each of the cited references do not disclose the claimed invention by arguing Hernandez-1 does not teach vancomycin is conjugated to the oligonucleotide and Greenwald does not teach oligonucleotide linkers.
Regarding Applicants’ second argument, in response to applicant's arguments against the references individually, 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). The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). Therefore, unobviousness cannot be shown merely by stating that none of the references teach all the claimed limitations.
Applicants argue that (3) there isn’t a reasonable expectation of success. It is argued that none of the cited reference provide any evidence that a polymer-drug conjugate of any form may selectively release the conjugated drug from the polymeric network while still retaining the drug’s activity. The claims as amended require that the cleavage product comprises the antimicrobial agent and a cleaved portion of the oligonucleotide retain antimicrobial activity. This alone is unpredictable. While Bossard refers to an oligonucleotide linker, it acknowledges that the conjugates may or may not possess a measurable degree of activity pointing to paragraph 0136. It is argued that Hernandez-1 avoids the uncertainty and unpredictability. Greenwald does not disclose the claimed conjugate. Greenwald discloses polymer-vancomycin conjugates for increasing the circulating life of vancomycin not polymer-drug conjugates that are part of a polymer network and has no relation to extending the circulating life of the drug because the drug is not in circulation when conjugated to the polymer. It is argued there is not a reasonable expectation of success because as disclosed by Bossard et al. the claimed cleavage product would not be expected to retain antimicrobial activity and second there is not a reasonable expectation that the polymeric network could be configured to allow diffusion of the released cleavage product.
Regarding Applicants’ third argument, firstly, with regards to the claimed cleavage product, Hernandez et al. teaches that the TT is the portion which is cleaved. Hernandez et al. also teaches that the TT can be shifted from the location center to the 5’ end which would allow for complete detachment (see page 9490, right column first paragraph). Therefore, depending on the location of the TT this would dictate the number of nucleotides which are attached to the cleaved vancomycin. Secondly, obviousness does not require absolute predictability, however, at least some degree of predictability is required. Evidence showing there was no reasonable expectation of success may support a conclusion of nonobviousness. NOTE: MPEP 2143.02. Here Applicants’ point to paragraph 0136 of Bossard et al. in an attempt to establish unpredictability. However, Applicants mischaracterize this paragraph. Paragraph 0136 states that the conjugate might not have activity not that the antimicrobial when cleaved does not have activity. Furthermore, this paragraph expressly states that the polymer conjugate possess anywhere from about 0.1% to about 100% or more of the antimicrobial activity of the unmodified parent amicrobial agent. Therefore, even if the conjugate possess less antimicrobial activity than the parent antimicrobial it still would have some activity. Furthermore, this paragraph expressly states that “conjugates possessing little or no activity contain a hydrolyzable linkage connecting the polymer to the antimicrobial agent, so that regardless of the lack of activity in the conjugate, the active antimicrobial agent (or a derivative thereof) is released upon aqueous-induced cleavage of the hydrolyzable linkage”. Furthermore, if one keeps reading the next paragraph 0137 states that conjugates possessing a hydrolytically stable linkage that couples the antimicrobial agent to the polymer, the conjugate will typically possess a measurable degree of activity. This means conjugates which are not hydrolytically cleaved would still be expected to possess activity. Therefore, the examiner cannot agree that Bossard et al. teaches that the activity of the vancomycin/antimicrobial following cleavage would be so unpredictable that one skilled in the art would not expect the vancomycin to possess activity. In fact, a fair reading of Bossard would suggest the opposite and Bossard expressly discloses that even conjugates with hydrolytically stable linkages would still be expected to retain some activity.
Regarding the arguments with regards to Greenwald and diffusion. Bossard et al. expressly teaches a hydrogel, which is the same structure taught in the instant specification. The examiner cannot agree that the structure as instantly claimed would be expected to increase the circulating life of the drug. By attachment to the polymer, this would necessarily happen as taught by Greenwald. The examiner cannot agree that the drug isn’t in circulation when attached to the polymer. As shown in paragraph 0006 of Greenwald, the extended circulating life is due to the hydrolysis of the polymer. Therefore, depending on how quickly the polymer hydrolysis dictates how long the drug remains in circulation. This also goes to the diffusion. In order for the vancomycin/antimicrobial to be released/diffuse from the hydrogel is predicated on the degradation rate. This is controlled by the polymer and the corresponding linkages as suggested by both Bossard et al. and Greenwald.
Applicants argue that (4) neither Hernandez-2 nor McNamara cure the deficiencies.
Regarding Applicants’ fourth argument, while this argument is considered it is not persuasive for the reasons set forth above.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ABIGAIL VANHORN whose telephone number is (571)270-3502. The examiner can normally be reached M-Th 6 am-4 pm EST.
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, Neil Hammell can be reached on 571-270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636
Prosecution Insights