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 Claims
The amendment submitted July 9, 2025 has been entered.
Claims 1-11, 15-18, 21-24, 27-30, and 38 are pending and under consideration.
Claims 12-14, 19-20, 25, and 31-37 were previously cancelled by Applicant.
Claim 26 is presently cancelled by Applicant.
Claims 1-3 and 7 are amended.
Claim 38 is new.
Claims 8-10, 15-18, 21-24, and 27-30 are withdrawn.
Claims 1-7, 11, and 38 are currently under examination and are the subject of this office action as explained below in the Election/Restriction section.
Election/Restrictions
Applicant’s election with traverse of Group I, claims 1-11 drawn to a compound of formula (I), a composition and combination containing formula (I), in the reply filed on December 17, 2024 is acknowledged.
The traversal is on the grounds that Applicant argues “independent claims 15 and 27 each depend from claim 1, which means they are commensurate in scope with claim 1 and therefore recite the same technical feature.” This is not found persuasive because Applicant is claiming a product, and more than one method of use, which are distinct processes and inventions.
The requirement is still deemed proper and is therefore made FINAL.
New claim 38 is drawn towards a compound of formula (I); therefore, is elected as part of Group I.
Applicant’s election of species with traverse of CSA-131 as a species of CSA in the reply filed on December 17, 2024 is acknowledged.
The traversal is on the grounds that Applicant argues “that there are many CSA compounds that would be expected to provide the same bone healing activity as CSA-131. In addition, the invention is the linkage of the CSA compound to a bone binding moiety via a linking moiety, not the selection of any particular CSA compound. Thus, the search will mainly focus on the bone binding moiety and the linking moiety such that considering other CSA compounds does not impose an undue burden on the Examiner”. This is not found persuasive because Applicant’s arguments are directed towards search burden, and the instant application is a national stage application submitted under 35 U.S.C. 371; therefore, unity of invention analysis, not independent and distinct analysis, which relies on search burden rationale under 35 U.S.C. 121 is applied.
As the response to restriction/election was incomplete, an examiner-initiated interview was attempted on March 13, 2025 via phone to complete the response and voicemail was left for the Attorney of Record.
As per the Requirement for Restriction/Election dated October 28, 2024, Applicant was requested to elect.
One specific CSA as per claim 2.
One specific bone-binding moiety as per claim 3.
One specific linker as per claim 7.
Applicant is reminded as per MPEP 818.01(b): “Election in reply to a requirement for restriction may be made either with or without an accompanying traverse of the requirement. A complete reply to a restriction requirement must include an election even if applicant traverses the requirement.”
The Attorney of Record provided a provisional election via voicemail on March 14, 2025 to complete the response by electing alendronate as the species of bone-binding moiety, NHS-PEG-COOH as a species of linker, and confirmed CSA-131 as an elected species of CSA.
Applicant confirmed the elections in Remarks submitted July 9, 2025.
The Examiner has reconsidered withdrawn claim 7 as per Applicant’s remarks, and has rejoined claim 7 as being directed to elected species.
The species election reads on claims 1-7, and newly presented claim 38.
(Please note: the elected species of linker does not read on claim 8 and the elected species of CSA does not read on claims 9-10).
For the purposes of compact prosecution, the search was expanded.
Consequently, claims 8-10, 15-18, 21-24, and 26-30 are withdrawn from further consideration pursuant to 37 CFR 1.142 (b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Claims 1-7, 11 and 38 are currently under examination and are the subject of this office action.
Information Disclosure Statement
No additional information disclosure statements have been submitted.
WITHDRAWN OBJECTIONS
The examiner withdraws objections to the specification based on corrections made by Applicant.
WITHDRAWN REJECTIONS
The examiner withdraws rejections to Claim 1-6 and 11 under 35 U.S.C. 112(a) based on claim amendments by Applicant.
The examiner withdraws rejections to Claim 2 under 35 U.S.C. 112(b) based on claim amendments by Applicant.
The examiner withdraws rejections to Claims 1, 2, 5, and 11 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Savage et al. (US20140271761 A1) based on claim amendments by Applicant.
The examiner withdraws rejections to Claims 1-6 and 11 under 35 U.S.C. 103 based on claim amendments by Applicant.
MAINTAINED/MODIFIED REJECTIONS
Claim Rejections - 35 USC § 112(b)
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.
Claim 3 remains 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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c).
In the present instance, claim 3 recites the broad recitation “etidronate, clodronate, tiludronate, pamidronate, medronate, etidronate, neridronate, olpadronate, alendronate, ibandronate, aminomethylene diphosphonate, risedronate, and zoledronate,” and the claim also recites “…preferably…is selected from the group consisting of alendronate, pamidronate and neridronate” and “more preferably…alendronate” which are narrower statements of the range/limitation.
Again, Applicant is reminded as per MPEP 2173.05 (d): “Description of examples or preferences is properly set forth in the specification rather than the claims. If stated in the claims, examples and preferences may lead to confusion over the intended scope of a claim. In those instances where it is not clear whether the claimed narrower range is a limitation, a rejection under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph should be made.”
Therefore, claim 3 remains rejected on grounds of indefiniteness.
NEW OBJECTIONS
Claim Objections
Claim 1 objected to because of the following informalities: At claim 1, line 7, the phrase “strait alkane,” should be “straight alkane”. Appropriate correction is required.
NEW REJECTIONS
Applicant’s claim amendments have necessitated new grounds of rejection.
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.
Claims 1-7, 11, and 38 are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al. (CN 10,4147,614 B)(English Machine Translation, “Chen”) in view of Genberg (USPN 9,931,350 B2)(“Genberg”) and further in view of Karpeisky et al. (USPN 10,046,055 B2).
Chen teaches that bisphosphonates, specifically alendronic acid can be functionalized using polyethylene glycol and the specific linker as in instant application (page 2, original document, top structures and bottom structure and shown below) for use in drug delivery.
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Consequently, Chen teaches compounds similar to claim 1 excepting the attachment of a CSA moiety. Chen also teaches the elements of claim 3 where the bisphosphonate is alendronate, and Chen also teaches the identical linker to instant invention, which is hydrophilic, has a molecular weight less than about 2kDa, and comprises PEG, meeting the claim limitations of claims 4-7.
Chen additionally teaches that “The surface of the calcium phosphate particles or calcium carbonate particles is covered with polyethylene glycol functionalized with alendronic acid. Polyalendronic acid-polyethylene glycol can firmly cover the surface of phosphate-gene particles, thereby effectively stabilizing nanoparticles for a long time and prolonging the time of circulation in the body (page 4, paragraph 5, English Machine Translation).”
Consequently, Chen teaches that alendronic acid can be PEGylated using the identical linker to the instant invention, and that such modification is beneficial in affording stability and improved bioavailability to the bisphosphonate.
Chen does not teach bioconjugates of alendronic acid with CSA moieties for combination therapy.
Chen also does not teach a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier.
Genberg teaches CSA compounds identical to the instant application and CSA compositions for treating bone infections and other bone diseases and conditions (Abstract and columns 19-24) as per claim 2, and 38.
Genberg also teaches the use of CSA compounds and pharmaceutical compositions and formulations in combination therapy with bisphosphonates; therefore, the elements of claim 11.
Specifically, Genberg teaches “In some embodiments, one or more CSA compounds are administered with additional compounds that provide therapeutic effects towards bone diseases or broken bones. In some embodiments, the CSA compound is administered with one or more bisphosphonates. Examples of bisphosphonates include Etidronate, Elodronate, Tiladronate, Pamidronate, Neridronate, Olpadronate, Alendronate, Ibandronate, Residronate, and/or Zoledronate (column 17, lines 13-20).”
Genberg also teaches that “The pharmaceutical composition may also be in the form of a solution of a salt form of the active ingredient in an appropriate aqueous vehicle, such as water or isotonic saline or dextrose solution. Also contemplated are compounds which have been modified by substitutions or additions of chemical or biochemical moieties which make them more suitable for delivery (e.g., increase solubility, bioactivity, palatability, decrease adverse reactions, etc.), for example by esterification, glycosylation, PEGylation, and complexation.”
Pertaining combination therapies, Genberg also teaches “As described herein, the methods of the embodiments also include the use of a compound or compounds as described herein together with one or more additional therapeutic agents for the treatment of disease conditions. Thus, for example, the combination of active ingredients may be: (1) co-formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by any other combination therapy regimen known in the art.
Bioconjugates are well-known in the art to be used as combination therapy regimens.
Karpeisky teaches bisphosphonate conjugates and pharmaceutical compositions containing bisphosphonate conjugates for treating bone diseases and conditions (Abstract).
Karpeisky also teaches the utility of bisphosphonates in treating bone disorders and diseases, and specifically alendronate: “Bisphosphonates are synthetic analogs of pyrophosphates characterized by a phosphorus-carbon-phosphorus backbone that renders them resistant to hydrolysis and are known to be useful in the treatment of these degenerative bone disorders. Bisphosphonates bind strongly to hydroxyapatite on the bone surface and act to reduce and inhibit the activity of osteoclasts; cells functioning in the absorption and removal of osseous tissue. The anti-resorptive effect of bisphosphonates is also mediated through effects on osteoblasts; cells that function in the production of bone. Thus, bisphosphonates are used clinically to inhibit bone resorption in disease states such as Paget's disease, osteoporosis, metastatic bone diseases, and malignant and nonmalignant hypercalcemia. Bisphosphonates that are currently used therapeutically include alendronate, clodronate, etidronate, pamidronate, tiludronate, ibandronate, zoledronate, olpadronate, residronate and neridronate (column 1, paragraphs 1-3).”
Karpeisky also teaches motivation for improving drug delivery for bisphosphonates to bone: “In the past, however, bisphosphonate therapies have frequently been accompanied by severe side effects such as retardation of bone development and somatic growth. Therefore, a need exists for novel bisphosphonate compounds that act as delivery vehicles to target and deliver therapeutic agents to bone and the surrounding soft tissue, allowing selective treatment of these tissues while eliminating or minimizing the severe side effects previously seen with bisphosphonate therapies (Column 1, lines 53-63).”
Karpeisky also teaches conjugates comprising bisphosphonates linked to an anti-infective for targeted bone delivery.
Specifically, Karpeisky teaches “Provided herein are bone-seeking conjugates containing anticancer or anti-infective compounds or derivatives thereof linked to bisphosphonates. When linked to a moiety having antineoplastic or anti-infective properties, bisphosphonates act as vehicles for the targeted delivery of these therapeutic entities to bone. The chemical bond(s) connecting the bisphosphonate and the drug is/are stable enough to survive in the bloodstream and yet is/are cleaved to liberate the drug when the conjugate binds to bone. Because these conjugates are capable of releasing anti-infective and cytotoxic components upon binding with bone tissue, they are useful in the treatment and prevention of bone cancer, bone infections, bone inflammation and disorders in soft tissues surrounding bone (Column 1, lines 66-67 and column 2, lines 1-19).”
Karpeisky teaches that the anti-infective can be an antibiotic or antimicrobial (column 2, lines 16-23) and that the bisphosphonate can be alendronate (column 1, lines 45).
Karpeisky does not specifically teach that the anti-infective can be a CSA moiety or that the linker specifically comprises PEG.
Consequently, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to have combined the teachings of Chen, Genberg and Karpeisky to access instant invention because Chen teaches the identical linker to instant invention and that bisphosphonates, specifically alendronic acid can be functionalized using polyethylene glycol and the identical PEG-based linker to improve stability and bioavailability, because Genberg teaches the identical CSAs and their pharmaceutical compositions can be administered in combination with bisphosphonates for combination therapy, including any other combination treatment regimen known in the art (i.e.: bioconjugation) and because Karpeisky teaches related bioconjugates containing bisphosphonates, linker and anti-infectives (i.e.: antibiotics) for use in treating bone disorders.
A person of ordinary skill in the art would be motivated to combine Chen’s teachings to incorporate a CSA moiety because the benefits of bisphosphonates as bone-binding moieties are well-known in the art for treating bone diseases and infection and taught by Karpeisky and Karpeisky teaches that” bisphosphonates act as vehicles for the targeted delivery” for anti-infectives such as antibiotics for bone. Genberg furthermore teaches additional therapeutic effects can be achieved via a combination therapy approach using CSA and bisphosphonates together, providing additional motivation to link both moieties via a linker as a targeted drug delivery strategy to bone.
Additionally, it would be furthermore prima facie obvious to develop pharmaceutical compositions using the compounds of formula (I) with pharmaceutically acceptable carriers as Chen, Genberg and Karpeisky all teach pharmaceutical compositions and formulations, which are highly predictable results that can be obtained with reasonable expectation of success.
Therefore, a person of ordinary skill would arrive at the claimed invention as a predictable result with a reasonable expectation of success based on the combined beneficial teachings of Chen, Genberg and Karpeisky.
Consequently, claims 1-7, 11 and 38 are rejected on grounds of obviousness.
Response to Arguments
The Remarks of July, 9 2025 have been fully considered but are not fully persuasive for the reasons below.
35 USC § 112(b)
Applicant’s Argument:
“Claims 2-3 are rejected under 35 U.S.C. 112(b) as being indefinite. Applicant amended claims 2 and 3 to remove the indefinite language, rendering the rejection moot.”
Examiner’s Response:
Applicant amended claim 2 to correct the deficiencies; however, claim 3 remains rejected for the reasons listed in the prior Office Action. Applicant has failed to amend claim 2 to remedy the issues identified previously with putting forth preferences in the claims and the broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim).
Consequently, for these reasons Applicant’s arguments are not found to be persuasive.
Conclusion
Claims 1-7, 11, and 38 are pending and are rejected.
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 CAROLYN L. LADD whose telephone number is (703)756-5313. The examiner can normally be reached M-Th, 7:00 am to 5:30 pm EST.
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/C.L.L./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622