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 .
Objections/Rejections Withdrawn
Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied, and constitute the complete set presently being applied to the instant application.
Response to Arguments
Applicant’s arguments with respect to claim(s) 1/12/2026 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Examiner’s Note
Agent Wexberg telephoned on 1/7/2026 and left a voicemail requesting clarification regarding the Nucleotide and/or Amino Acid Sequence Disclosure compliance issue with regards to the Figures. Examiner Konopelski Snavely in turn left a voicemail saying that the object was made in error. It has been removed from this current Office Action.
Claim Status
Claims 1, 3-5, 7-9, 13, 15 and 60-64 are pending under examination. Claim 1, 3-5, 7-9, and 60-63 are currently amended. Claims 2, 6, 10-12, 14, and 16-59 are cancelled. Claims 13, 15 and 64 were previously presented.
Priority
The instant application is the 371 national stage entry of PCT/US2020/017301, filed 2/7/2020, which claims priority to the provisional application 62/802,616, filed 2/7/2019. The priority date of 2/7/2019 is acknowledged.
Claim Objections
Claim 1 is objected to because of the following informalities: lines 2-3 recite “to the individual at a site need of bone repair.” Amend the claim such that it reads “to the individual at a site in need of bone repair” (emphasis added). Appropriate correction is required.
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.
Claim(s) 1, 3-5, 7-8, 13, and 61-64 are rejected under 35 U.S.C. 103 as being unpatentable over Caplan (WO 2013/033043 A1, published 7/3/2013) in view of Yano et al. (Functional expression of beta-chemokine receptors in osteoblasts: role of regulated upon activation, normal T cell expressed and secreted (RANTES) in osteoblasts and regulation of its secretion by osteoblasts and osteoclasts. Endocrinology. 2005 May;146(5):2324-35.) and Roberts (Uncovering the periosteum for skeletal regeneration: the stem cell that lies beneath. Bone. 2015 Jan;70:10-8.).
Caplan teaches methods of isolating perivascular medicinal cells (PVMCs) as well as compositions and methods of use thereof (Abstract). PVMCs can secrete trophic factors such as CCL5/RANTES ([0020, 00217, 00221, 00238, 00242]). Localized perivascular cells may play a role in physiological bone healing (i.e. callus formation). A bone injury may include a broken bone, characterized by a separation between two pieces of bone that were formerly joined. The gap created between the two pieces fills with mesenchymal progenitor cells that differentiate into cartilage or allow blood vessels to span the break. In some embodiments, PVMCs may be used to fulfill the role of mesenchymal progenitor cells ([0036-0037]).
Caplan further teaches methods of reconstructing bone tissue comprising administering a composition comprising a therapeutically effective amount of PVMCs to a subject in need thereof ([00271]). Caplan also teaches a method of treating a disease that affects cellular function, wherein the disease is bone fractures [00261]) as well as a method of modulating bone formation ([00274], claim 22), which involve similarly administering PVMCs.
Caplan does not explicitly teach that the CCL5 administered is isolated.
Yano teaches that RANTES (CCL5) has been shown to induce osteoblast chemotaxis and RANTES receptors are expressed in primary calvarial osteoblasts and MC3T3-E1 cells, in which RANTES promotes cell migration and survival; further, RANTES can promote cell migration secreted from osteoclast in a paracrine mode of action (Pg 2325, left column, second paragraph). Yano teaches administering of exogenous RANTES to primary calvarial osteoblasts and MC3T3-E1 cells (Pg 2325, right column, “[125-I]-RANTES binding assay”, first paragraph; Pg 2326, right column, “Determination of chemotactic activity using a chemotaxis bioassay”).
Roberts teaches that bone repair is mediated by osteoblasts, which form woven bone at the break site (Pg 12, “Bone repair: the cellular picture”).
In summary, Caplan teaches a method of bone repair through administration of PVMCs that secrete CCL5. Yano teaches that administration of exogenous (isolated) CCL5 to aid in osteoblast chemotaxis and survival, cells which are necessary for bone repair, and Roberts teaches that osteoblasts are involved in bone repair after breaks. Therefore, regarding claims 1 and 8, it would be prima facie obvious to administer isolated CCL5 in a method of treating bone repair. One skilled in the art would be motivated to do so to attract osteoblasts to the site of bone injury and further encourage bone repair and healing. One would have a reasonable expectation of success as Caplan previously established that bone repair could be similarly induced through administration of PMVCs that secrete CCL5.
Regarding claims 3 and 4, Caplan further teaches CCL5 secreted from isolated PVMCs can be encased in a scaffold prior to therapeutic administration ([00233]). The scaffold material comprises calcium phosphate ceramics, degradable polymers, collagen sponges or combination thereof.
Regarding claim 5, Caplan does not explicitly teach administering at least about 1-100ng of CCL5. However, Caplan does teach the precise effective amount for a subject will depend upon the subject’s size and health, the nature and extent of the condition, and the therapeutics or combination of therapeutics selected for administration. Thus, it is not useful to specify an exact effective amount in advance. However, the effective amount for a given situation is determined by routine experimentation and is within the judgment of the clinician ([00231]). Thus, regarding claim 5, although Caplan does not explicitly teach administering about 1-100ng of CCL5, it would have been prima facie obvious to one of ordinary skill in the art because Caplan recognized that the therapeutically effective amount to be administered to a subject in need thereof depends on the unique healthy and physiology of the subject as well as the nature and extent of the condition, factors to be determined at the time of treatment. Thus, it would have been obvious to optimize the amount of CCL5 administered to a subject in need thereof in order to achieve a desirable therapeutic outcome.
Regarding claim 7, Caplan further teaches that CCL5 secreted from PVMCs can be administered in conjunction with a pharmaceutically acceptable carrier; the composition can be administered through direct tissue injection or by direct application to the area as needed [00267]).
Regarding claim 13, Caplan further teaches that the effect or impact of the therapeutically effective amount administered to a subject in need thereof can be detected by chemical markers or antigen levels, for example (monitored).
Regarding claims 61-64, Caplan further teaches that CCL5 secreted from PVMC preparations may be administered with a wide variety of additional elements such as BMP-2-containing collagen sponge, BMP-2 and BMP-7 containing sponge, or combinations thereof ([00282]).
Claim(s) 1, 3-5, 7-9, 13, 15, and 61-64 are rejected under 35 U.S.C. 103 as being unpatentable over Caplan (WO 2013/033043 A1, published 7/3/2013), Yano et al. (Functional expression of beta-chemokine receptors in osteoblasts: role of regulated upon activation, normal T cell expressed and secreted (RANTES) in osteoblasts and regulation of its secretion by osteoblasts and osteoclasts. Endocrinology. 2005 May;146(5):2324-35.), and Roberts (Uncovering the periosteum for skeletal regeneration: the stem cell that lies beneath. Bone. 2015 Jan;70:10-8.), as applied to claims 1, 3-5, 7-8, 13, and 61-64 above, and further in view of Chinese Orthopaedic Association (COA) (Diagnosis and treatment of osteoporotic fractures. Orthop Surg. 2009 Nov;1(4):251-7.).
The teachings of Caplan, Yano, and Roberts have been set forth above. Caplan, Yano, and Roberts do not teach a method of administering at least one cytokine and at least one additional therapy wherein the therapy comprises surgical repair, fixation of a device to set the site in need, placing the individual in a cast or sling, or a combination thereof.
COA teaches that osteoporosis is a systemic, metabolic skeletal disease charactered by reduced bone quality and decreased bone mass with destruction and deterioration of bone microstructure (Pg 251, first column, first paragraph under “Overview”). COA further teaches common sites of fractures include the spine, hip, distal radius, and proximal humerus, which can be fixed through surgical repair or non-surgical methods such as slings, braces, or other means of immobilization (Pg 253-255, starting at “4. Common sites, features and surgical treatment of osteoporotic fracture”).
Thus, regarding claims 9 and 15, Caplan, Yano, and Roberts teach a method of inducing bone repair comprising administering at least one cytokine, CCL5, to an individual at a site in need of bone repair. COA teaches that individuals with osteoporosis are susceptible to bone fractures at several locations throughout the body that can be treated through either surgical repair or immobilization means (splint, etc.). Therefore, it would be prima facie obvious to combine the aforementioned methods of treatment in order to improve treatment efficacy. One skilled in the art would have a reasonable expectation of success as it was already established that both surgery and immobilization could be used to treat bone fractures in osteoporotic patients.
Claim(s) 1, 3-5, 7-8, 13, and 60-64 are rejected under 35 U.S.C. 103 as being unpatentable over Caplan (WO 2013/033043 A1, published 7/3/2013), Yano et al. (Functional expression of beta-chemokine receptors in osteoblasts: role of regulated upon activation, normal T cell expressed and secreted (RANTES) in osteoblasts and regulation of its secretion by osteoblasts and osteoclasts. Endocrinology. 2005 May;146(5):2324-35.), and Roberts (Uncovering the periosteum for skeletal regeneration: the stem cell that lies beneath. Bone. 2015 Jan;70:10-8.), as applied to claims 1, 3-5, 7-8, 13, and 61-64 above, and further in view of Einhorn (Einhorn TA, Gerstenfeld LC. Fracture healing: mechanisms and interventions. Nat Rev Rheumatol. 2015 Jan;11(1):45-54.).
The teachings of Caplan, Yano, and Roberts have been set forth above. Caplan, Yano, and Roberts do not teach a method of administering both CCL5 and Wnt.
Einhorn teaches local strategies for the repair and regeneration of bone include the use of osteogenic materials, including peptide signaling molecules such as Wnt proteins, which has great therapeutic potential to enhance skeletal repair (Pg 5, “Local biological enhancement”).
Thus, regarding claim 60, Caplan, Yano, and Roberts teach a method of inducing bone repair comprising administering at least one cytokine, CCL5, to an individual at a site in need of bone repair. Einhorn teaches that Wnts are useful for the repair and generation of bone. Therefore, it would be prima facie obvious to include Wnts in a method of inducing bone repair. One skilled in the art would have a reasonable expectation of success as it was already established that local repair strategies utilized Wnts to therapeutically enhance skeletal repair.
Conclusion
No claim is 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 Sara E Konopelski Snavely whose telephone number is (571)272-1841. The examiner can normally be reached Monday - Friday 9-6pm EST.
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/SARA E KONOPELSKI SNAVELY/Examiner, Art Unit 1658
/FRED H REYNOLDS/Primary Examiner, Art Unit 1658