DETAILED ACTION
Receipt is acknowledged of applicant’s Response to Restriction Requirement filed 12/15/2025.
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 the Claims
No claims are amended or newly added. Claims 6-8, 10, 11, 14, 19, 23-25 , 27, 28 and 31 are cancelled. Accordingly, claims 1-5, 9, 12, 13, 15-18, 20-22, 26, 29, 30, 32 and 33 remain pending in the application.
Election/Restrictions
Claims 20-22, 26, 29, 30, 32 and 33 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 12/15/2025.
Accordingly, claims 1-5, 9, 12, 13 and 15-18 are currently under examination.
Information Disclosure Statement
The IDS filed 10/11/2023 has been considered. A signed copy is enclosed herewith.
Claim Objections
Claim 1 is objected to because of the following informalities: the claim recites, “skeletal stem cells” as well as “SSCs”. When using acronyms, it is conventional to follow the expanded phrase with the acronym in parentheses and then recite only the acronym thereafter. Thus, it is suggested that “(SSCs)” is inserted immediately after “skeletal stem cells” in line 3 of the claim. Appropriate correction is requested.
Claim Rejections - 35 USC § 112
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 12, 17 and 18 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 12 recites the limitation "the implant" in the 1st line of the claim. Claim 12 depends from claim 2 and ultimately claim 1. Neither claim 1 nor claim 2 recite “an implant”. Thus, there is insufficient antecedent basis for this limitation in the claim.
Claim 17 recites the limitation "the drug delivery device" in the 1st line of the claim. Claim 17 depends from claim 2 and ultimately claim 1. Neither claim 1 nor claim 2 recite “an drug delivery device”. Thus, there is insufficient antecedent basis for this limitation in the claim.
Claim 18 recites the limitation "the implant" in the 1st line of the claim. Claim 18 depends from claim 2 and ultimately claim 1. Neither claim 1 nor claim 2 recite “an implant”. Thus, there is insufficient antecedent basis for this limitation in the claim.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 1-4, 12, 17 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Yue et al. (“BMP2 Gene Therapy on the Repair of Bone Defects of Aged Rats”, Calcif Tissue Int (2005) 77:395-403, hereafter as “Yue”) in view of Peng et al. (US 2019/0308949 A1, Oct. 10, 2019, hereafter as “Peng”).
The claimed invention is drawn to a method for improving bone regeneration in an aged mammal, the method comprising: contacting skeletal stem cells with a combination of factors that reactivate aged SSCs and concurrently abate crosstalk to hematopoietic cells favoring an inflammatory milieu. It is noted that “contacting” is not explicitly defined in the instant specification and, as such, is being given its broadest reasonable interpretation as encompassing indirect and direct contact.
Regarding instant claims 1-3, Yue teaches a method for improving bone regeneration in an aged mammal, the method comprising: contacting skeletal stem cells with a combination of factors that reactivate aged SSCs (abstract, Age-related decline in the number of mesenchymal stem cells (MSCs) and their reduced capability to differentiate osteogenically, along with diminished availability of growth factors, may be major factors accounting for reduced bone formation in the aging mammalian body.; pg. 398, col 1, para 2, The relationships between age and number of CFUs and ALP-positive CFUs were determined on day 10 ... a significant decrease in the number of ALP-positive CFUs with increasing age.; pg. 398, col 2, para 2-3, Since it has been well demonstrated that BMP2 can induce MSCs to differentiate into an osteoblast phenotype, we analyzed the osteogenic differentiation capability of Adv-BMP2-transfected cells of different ages ... These combined data suggest that after being transfected with Adv-BMP2, MSCs from aged animals - similar to MSCs from juvenile and adult animals - are able to (1) secrete functional human BMP2 and (2) be induced to secrete osteoblast characteristic proteins in vitro.; pg. 401, col 2, para 3, Our data show that MSCs from aged rats can restore their osteogenic potential following BMP2 gene transduction. It can be suggested that ex vivo expansion and genetic engineering of MSCs is a useful approach for future treatment of age-related osteoporotic fractures and delayed healing.; Note, The teaching by Yue "BMP2 can induce MSCs to differentiate into an osteoblast phenotype" describes the "skeletal stem cells" of the instant claims. See instant Specification para [0088], Skeletal stem cells can be reprogrammed from non-skeletal cells, including without limitation mesenchymal stem cells.). Yue also teaches filling (implanting) a bone defect with a block of β-tricalcium phosphate (TCP) and BMP2 gene-transfected MSC’s or β-gal-transfected MSCs (pg. 397; left col. para. 3-4).
Yue does not specifically teach an inhibitor of CSF1.
Peng teaches a method for treating various diseases including bone-related diseases comprising administering CSF1 inhibitors (abstract; [0099]; para [0009], certain quinoxaline compounds can inhibit activities of type III RTKs (e.g., PDGFRα, PDGFRβ, FLT3, c-KIT and CSF-1R).; [0102], useful for the treatment of autoimmune disorders and inflammatory diseases include, but are not limited to ... osteoporosis.; [0099], The osteoporosis may be attributed to (I) menopause in women, (2) aging in men or women). Peng teaches that a pharmaceutical composition comprising said inhibitors can be administered via an implanted reservoir (implant; [0110]).
Both Yue and Peng are drawn to treating bone related diseases in aged subjects, thus, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to include administration of a CSF1 inhibitor as suggested by Peng into the method for improving bone regeneration in an aged mammal of Yue with a reasonable expectation of success. A skilled artisan would have been motivated to do so because Yue teaches that CSF1 signaling pathway mediated inflammatory bone erosion (para [0003], Because of its role in osteoclast biology, CSF-1R is also an important therapeutic target for osteoporosis, inflammatory arthritis, and other inflammatory bone erosion.).
With regards to the limitation “that reactivate aged SSCs and concurrently abate crosstalk to hematopoietic cells favoring an inflammatory milieu”, said limitation is the intended result of the process step positively recited. Yue and Peng suggests the method step of contacting skeletal stem cells with a combination of factors, i.e., BMP2 activating agent and CSF1 inhibitor. Accordingly, such a limitation in a method claim is not given weight when it simply expresses the intended result of a process step positively recited (MPEP 2111.04(I)). The references meet the limitation.
Regarding instant claim 4, Yue and Peng teach the elements discussed above. No other bioactives are required in Yue and Peng. Thus, the references meet the limitation, “the drug delivery device comprises as the sole active agents a BMP2 activating agent and a CSF1 inhibitor”.
Regarding instant claim 12, Yue and Peng teach the elements discussed above. Yue also teaches filling (implanting) a bone defect with a block of β-tricalcium phosphate (TCP) and BMP2 gene-transfected MSC’s or β-gal-transfected MSCs (i.e., biodegradable; pg. 397; left col. para. 3-4).
Regarding instant claim 17, Yue and Peng teach the elements discussed above. Yue also teaches filling (implanting) a bone defect with a block of β-tricalcium phosphate (TCP) and BMP2 gene-transfected MSC’s or β-gal-transfected MSCs, wherein the MSCs are autologous (i.e., not exogenous; pg. 397; left col. para. 3-4).
Regarding instant claim 18, Yue and Peng teach the elements discussed above. Yue also teaches that the implant was provided immediately following a local acute injury (pg. 397, 2nd para.).
Thus, the combined teachings of Yue and Peng render the instant claims prima facie obvious.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Yue et al. (“BMP2 Gene Therapy on the Repair of Bone Defects of Aged Rats”, Calcif Tissue Int (2005) 77:395-403, hereafter as “Yue”) in view of Peng et al. (US 2019/0308949 A1, Oct. 10, 2019, hereafter as “Peng”), as applied to claims 1 and 2 above, and further in view of Chan et al. (US 2017/0360838 A1, Dec. 21, 2017, hereafter as “Chan”).
The claimed invention is described above.
Yue and Peng teach the elements discussed above including human BMP2 (Yue at pg. 400, left col).
Yue and Peng are silent to human BMP2 protein in a dose of about 50 µg to about 10 mg.
Chan teaches compositions and methods thereof for producing functional chondrocytes, skeletal cells, bone marrow stromal cells, and progenitor cells for the purpose of treating human disorders of the cartilage, bone and hematopoietic system, and in the regeneration of aged or otherwise damaged cartilage and bone (abstract; [0008]). Chan teaches in some embodiments, a dose of BMP2 is provided in an implant and that the effective dose may be determined based on the specific tissue, rate of release from the implant, size of the implant, and the like and may be empirically determined by one of skill in the art ([0086]). Exemplary dosages taught include 100 µg, 1 mg, 5 mg and 10 mg ([0086]). Chan teaches that the BMP2 is from a human source ([0010]-[0012]).
The references are all drawn to implants comprising factors for the treatment of bone-related disorders, thus, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize the amount of human BMP2 and arrive at a dose of about 50 µg to about 10 mg by way of routine experimentation into the invention of Yue/Peng as suggested by Chan with a reasonable expectation of success. A skilled artisan would have been motivated to do so because Chan teaches suitable dosages and the parameters in which to arrive at an effective dose and it is also the normal desire of scientists or artisans to improve upon what is already generally known to determine where in a disclosed set of dosages is the optimum dosages.
Thus, the combined teachings of Yue, Peng and Chan render the instant claim prima facie obvious.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Yue et al. (“BMP2 Gene Therapy on the Repair of Bone Defects of Aged Rats”, Calcif Tissue Int (2005) 77:395-403, hereafter as “Yue”) in view of Peng et al. (US 2019/0308949 A1, Oct. 10, 2019, hereafter as “Peng”), as applied to claims 1 and 2 above, and further in view of Hume et al. (“Therapeutic applications of macrophage colony-stimulating factor-1 (CSF-1) and antagonists of CSF-1 receptor (CSF-1R) signaling”, Blood, 23 February 2012, Vol. 119, No. 8, pp. 1810-1820; hereafter as “Hume”).
The claimed invention is described above.
Yue and Peng teach the elements discussed above.
Yue and Peng are silent to the limitation, “wherein the CSF1 inhibitor is an antibody specific for CSF1 or CSF1R provided at a dose of form about 20 µg to about 5 mg”.
Hume teaches that macrophage-colony stimulating factor (CSF-1) signaling through its receptor (CSF-1R) promotes the differentiation of myeloid progenitors into heterogeneous populations of monocytes, macrophages, dendritic cells, and bone-resorbing osteoclasts and macrophage populations elicited by CSF-1 are associated with, and exacerbate, a broad spectrum of pathologies, including cancer, inflammation, and bone disease (abstract). Hume teaches there are different approaches to inhibiting the action of CSF-1 including antibodies against the receptor and antibodies against the ligand (page 1814, right col.). Hume teaches exemplary dosages of CSF-1 and CSF-1R inhibitors including 1-2 mg (pages 1815-1816).
Hume and Peng are drawn to administering CSF1 and CSF1R inhibitors for the treatment of various diseases including bone-related diseases, thus, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to include the particular CSF1 or CSF1R inhibitors, antibodies specific for CSF1 or CSF1R in a dose of 1-2 mg into the invention of Yue/Peng as suggested by Hume with a reasonable expectation of success. A skilled artisan would have been motivated to do so because Hume teaches suitable dosages of antibodies specific for CSF1 or CSF1R for the purpose of inhibiting CSF1 or CSF1R.
Thus, the combined teachings of Yue, Peng and Hume render the instant claim prima facie obvious.
Claims 13, 15 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Yue et al. (“BMP2 Gene Therapy on the Repair of Bone Defects of Aged Rats”, Calcif Tissue Int (2005) 77:395-403, hereafter as “Yue”) in view of Peng et al. (US 2019/0308949 A1, Oct. 10, 2019, hereafter as “Peng”), as applied to claims 1, 2 and 12 above, and further in view of Guze et al. (US 2012/0253470 A1, Oct. 4, 2012, hereafter as “Guze”).
The claimed invention is described above.
Yue and Peng teach the elements discussed above.
Yue and Peng are silent to the particular biodegradable implant materials of instant claims 13, 15 and 16.
Guze teaches implantable compositions for promoting bone growth or regeneration comprising bioactive agents and biodegradable scaffold materials (abstract, [0009] and [0033]-[0034]). Guze teaches particular bioactive agents including BMP2 ([0013]) and particular scaffold materials including PCL, PLGA, collagen, hyaluronic acid, cellulose, chitosan, silk, gelatin, elastin or a hydrogel ([0069], [0182] and [0197]). Guze teaches that the biodegradable scaffold releases the bioactive agents to the environment where the scaffold is placed ([0033]).
The references are all drawn to treating bone related diseases/promoting bone regeneration, thus, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to include the particular biodegradable implant materials, PCL, PLGA, collagen, hyaluronic acid, cellulose, chitosan, silk, gelatin, elastin or a hydrogel into the invention of Yue/Peng as suggested by Guze with a reasonable expectation of success. A skilled artisan would have been motivated to do so because Guze teaches that said PCL, PLGA, collagen, hyaluronic acid, cellulose, chitosan, silk, gelatin, elastin are all suitable biodegradable implant materials for the purpose releasing bioactives such as BMP2 and promoting growth and regeneration of bone.
Thus, the combined teachings of Yue, Peng and Guze render the instant claim prima facie obvious.
Conclusion
All claims have been rejected; no claims are allowed.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CASEY HAGOPIAN whose telephone number is (571)272-6097. The examiner can normally be reached on M-F 9:00 am - 5:00 pm.
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/CASEY S HAGOPIAN/Examiner, Art Unit 1617