DETAILED ACTION
Receipt is acknowledged of applicant’s Amendment/Remarks filed June 11, 2026.
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
Claims 1, 4, 5, 9, 12, 17 and 18 have been amended. Claims 2, 3, 6-8, 10, 11, 14 and 19-33 have been cancelled. Claims 34-39 are newly added. Accordingly, claims 1, 4, 5, 9, 12, 13, 15-18 and 34-39 remain pending in the application and are currently under examination.
Information Disclosure Statement
The listing of references in [00148]-[00213] of the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Withdrawn Objections/Rejections
Applicant’s amendment renders the objection of claim 1 moot. Specifically, the claim has been amended to remedy the minor informality. Thus, said objection has been withdrawn.
Applicant’s amendment renders the rejections of claims 12, 17 and 18 under 35 USC 112(b) moot. Specifically, the claims have been amended to remedy the antecedent basis issues. Thus, said rejections have been withdrawn.
Applicant’s amendment renders the rejection of claims 1-4, 12, 17 and 18 under 35 USC 103 over Yue in view of Peng moot. Specifically, independent claim 1 has been amended to include the limitation, “for improving bone regeneration in an aged human” which is not explicitly taught by Yue. Thus, said rejection has been withdrawn. However, after further consideration, a new grounds of rejection is made under 35 USC 103 over, Yue, Peng and Lelovas. Additionally, claim 4 has been amended into an independent claim and incorporates the limitations of claim 5 and 9. Said limitations of claims 5 and 9 are taught by Yue and Peng. Accordingly, a new grounds of rejection is made under 35 USC 103 over, Yue, Peng, Chan and Hume.
Applicant’s amendment renders the rejection of claim 5 under 35 USC 103 over Yue in view of Peng and Chan moot. Specifically, independent claim 1 has been amended to include the limitation, “for improving bone regeneration in an aged human” which is not explicitly taught by Yue. Thus, said rejection has been withdrawn. However, after further consideration, a new grounds of rejection is made under 35 USC 103 over, Yue, Peng, Lelovas and Chan.
Applicant’s amendment renders the rejection of claim 9 under 35 USC 103 over Yue in view of Peng and Hume moot. Specifically, independent claim 1 has been amended to include the limitation, “for improving bone regeneration in an aged human” which is not explicitly taught by Yue. Thus, said rejection has been withdrawn. However, after further consideration, a new grounds of rejection is made under 35 USC 103 over, Yue, Peng, Lelovas and Hume.
Applicant’s amendment renders the rejection of claims 13, 15 and 16 under 35 USC 103 over Yue in view of Peng and Guze moot. Specifically, independent claim 1 has been amended to include the limitation, “for improving bone regeneration in an aged human” which is not explicitly taught by Yue. Thus, said rejection has been withdrawn. However, after further consideration, a new grounds of rejection is made under 35 USC 103 over, Yue, Peng, Lelovas and Guze.
New Rejections
In light of Applicant’s amendments, the following rejections have been newly added:
Claim Objections
Claim 4 is objected to because of the following informalities: the claim recites, “implanted a a targeted” at line 3 of the claim. There appears to be a typographical error. Appropriate correction is requested.
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, 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”) and Lelovas et al. (“The Laboratory Rat as an Animal Model for Osteoporosis Research”, Comp Med. 2008 Oct; 58(5):424-430; hereafter as “Lelovas”).
The claimed invention is drawn to a method for improving bone regeneration in an aged human, the method comprising: contacting skeletal stem cells (SSC) with a drug delivery device implanted at a targeted skeletal site, the device comprising human BMP2 protein and an inhibitor of SCF1 in a dose effective to 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 claim 1, 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]). Peng teaches that the subject in need of treatment can be a mammal, wherein the term “mammal” encompasses humans ([0109]).
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 regard to the limitation, “... in an aged human”, Yue teaches that the process of aging is accompanied by a disequilibrium between bone formation and bone resorption, resulting in age-related bone loss and osteoporosis, leading to an increased incidence of osteoporotic fractures, the healing of which is slowed in aged humans and mammals and utilizes human BMP2 in Experiment I (page 395, left col., last para.; page 396, right col., 3rd para.) and Peng teaches that the subject in need of treatment can be a mammal, wherein the term “mammal” encompasses humans ([0109]). However, Yue does not explicitly teach delivering BMP2 to a human.
Lelovas teaches that osteoporosis is an important systemic disorder, affecting mainly Caucasian women, with a diverse and multifactorial etiology (abstract). A large variety of animal species, including rodents, rabbits, dogs, and primates, have been used as animal models in osteoporosis research (abstract). Among these, the laboratory rat is the preferred animal for most researchers (abstract). The similarities in pathophysiologic responses between the human and rat skeleton, combined with the husbandry and financial advantages, have made the rat a valuable model in osteoporosis research (page 428 – Conclusions).
Yue and Lelovas teach utilizing a rat model in osteoporosis research, 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 treat a human subject by delivering BMP2 in the invention of Yue, as suggested by Lelovas, with a reasonable expectation of success. A skilled artisan would have been motivated to do so because Lelovas teaches that that the laboratory rat is the preferred animal in osteoporosis research largely because of the similarities in pathophysiologic responses between the human and rat skeleton in combination with the husbandry and financial advantages.
With regards to the limitation “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. The combined references suggest the method step of contacting skeletal stem cells with a drug delivery device comprising human BMP2 activating agent and an 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 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, Peng and Lelovas render the instant claims prima facie obvious.
Response to Arguments
Applicant's arguments, filed June 11, 2026, regarding the 103 rejection over Yue and Peng have been fully considered and they are persuasive in part. Thus, the rejection has been withdrawn and replaced with a new grounds of rejection utilizing the same references. Thus, applicant’s arguments are relevant to the new rejection and, as such, are addressed below.
Applicant argues that there is no teaching in Yue of the effect of BMP2 on endogenous SSC – only the growth of a highly manipulated cell population. Applicant also states that experimental data has been provided demonstrating the BMP2 alone is not sufficient to reinstate youthful bone regeneration in aged bones, but that a combination of BMP2 and anti-Csf1 is required. Remarks, page 7.
In response, it is respectfully submitted that Yue teaches implantation of an MSC/TCP (loaded with BMP2) composite into a femoral defect site and bone regeneration was assessed (page 397, right col., 2nd para.). Yue teaches that the data suggests 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 (page 398, right col. 3rd para.). Yue also teaches that MSCs from aged rats genetically modified to express recombinant human BMP2 (rhBMP2) have the potential to regenerate bone, thus enhancing the healing of defects (page 400, left col. last para). Thus, contrary to applicant’s assertion, Yue’s data suggests implantation of an MSC/TCP (loaded with BMP2) composite into a bone defect site has the potential to regenerate bone and enhance healing of said defect. Additionally, if applicant is making an assertion of unexpected results, please refer to MPEP 716.02(b) which details the burden on Applicant to establish that results in a side-by-side comparison to the closest prior art are unexpected and significant. Specifically, Applicant must establish that differences in results are in fact unexpected and unobvious and are of both practical and statistical significance. Evidence of unexpected properties must also be commensurate in scope with the claims. For these reasons, applicant’s argument is unpersuasive.
Applicant argues that the secondary reference does not remedy the deficiencies of the primary reference. Applicant asserts that a blanket indication (treatment of osteoporosis using a Csf1 inhibitor) in Peng is untrue because Csf1 deficient animals show decreased mechanical strength in bone healing. Applicant asserts that it is only the specific, local, administration of the combined factors that there is a reinstatement of youthful healing. Remarks, pages 7-8.
In response, it is respectfully submitted that Peng teaches a method for treating various diseases including bone-related diseases (e.g., osteoporosis) comprising administering CSF1 inhibitors. Peng teaches that a pharmaceutical composition comprising said inhibitors can be administered via an implanted reservoir (i.e., local administration). Both Yue and Peng are drawn to treating bone related diseases in aged subjects, thus, it would have been obvious to combine the teachings of Yue and Peng and arrive at the claimed invention. However, a prima facie case of obviousness can be rebutted when evidence of unexpected results is presented. It is applicant’s burden to establish that results in a side-by-side comparison to the closest prior art are unexpected and significant and said evidence must also be commensurate in scope with the claimed invention. See MPEP 716.02(a)-(e) for details. For these reasons, applicant’s argument is unpersuasive.
Thus, for these reasons, Applicant’s arguments are found unpersuasive.
Claims 4, 34, 38 and 39 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”), Chan et al. (US 2017/0360838 A1, Dec. 21, 2017, hereafter as “Chan”) and 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 drawn to a method for improving bone regeneration in an aged mammal, the method comprising: contacting skeletal stem cells (SSC) with a drug delivery device implanted a a targeted skeletal site, the device comprising as the sole active agents human BMP2 protein and an inhibitor of CSF1 in a dose effective to reactivate aced SSCs and concurrently abate crosstalk to hematopoietic cells favoring an inflammatory milieu, wherein the human BMP2 protein is provided at a unit dose of from about 50 µg to about 10 mg and the CSF1 inhibitor is an antibody specific for CSF1 or CSF1 R provided at a dose of from about 20 µg to about 5 mg.. 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 claim 4, 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]). Peng teaches that the subject in need of treatment can be a mammal, wherein the term “mammal” encompasses humans ([0109]).
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.). It is noted that no other bioactives are required in Yue and Peng. Thus, the references meet the limitation, “the device comprising as the sole active agents human BMP2 protein and an inhibitor of CSF1”.
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.
Yue and Peng are also 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.
With regards to the limitation “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. The combined references suggest the method step of contacting skeletal stem cells with a drug delivery device at a targeted skeletal site, the device comprising a human BMP2 activating agent and a 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 34, 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 38, 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 39, 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, Peng, Chan and Hume render the instant claims prima facie obvious.
Response to Arguments
Applicant's arguments filed, June 11, 2026, regarding the 103 rejection over Yue and Peng (as it applies to claim 4) have been fully considered and persuasive in part. Thus, the rejection has been withdrawn and replaced with a new grounds of rejection utilizing the same references. Thus, applicant’s arguments are relevant to the new rejection and, as such, are addressed below.
Applicant argues that Yue teaches the implantation of genetically modified cells and, as such, does not read on the limitation, “sole active agents”. Remarks, page 8.
In response, it is respectfully submitted that the instant specification does not define what is included or excluded as an active agent. Yue 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). The MSC’s are being interpreted as a carrier to the BMP2 and not an active agent.
Thus, for these reasons, Applicant’s arguments are found unpersuasive.
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”) and Lelovas et al. (“The Laboratory Rat as an Animal Model for Osteoporosis Research”, Comp Med. 2008 Oct; 58(5):424-430; hereafter as “Lelovas”), as applied to claim 1 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, Peng and Lelovas teach the elements discussed above including human BMP2 (Yue at pg. 400, left col).
Yue, Peng and Lelovas 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/Lelovas 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, Lelovas and Chan render the instant claim prima facie obvious.
Response to Arguments
Applicant's arguments, filed June 11, 2026, regarding the 103 rejection over Yue, Peng and Chan have been fully considered but they are not persuasive.
Applicant relies on the same arguments as presented for the 103 rejection over Yue and Peng. No further arguments regarding claim 5 are presented. Remarks, page 8.
For the same reasons as discussed above, Applicant’s arguments are not persuasive.
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”) and Lelovas et al. (“The Laboratory Rat as an Animal Model for Osteoporosis Research”, Comp Med. 2008 Oct; 58(5):424-430; hereafter as “Lelovas”), as applied to claim 1 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, Peng and Lelovas teach the elements discussed above.
Yue, Peng and Lelovas 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/Lelovas 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. Lelovas and Hume render the instant claim prima facie obvious.
Response to Arguments
Applicant's arguments, filed June 11, 2026, regarding the 103 rejection over Yue, Peng and Hume have been fully considered but they are not persuasive.
Applicant relies on the same arguments as presented for the 103 rejection over Yue and Peng. No further arguments regarding claim 9 are presented. Remarks, page 9.
For the same reasons as discussed above, Applicant’s arguments are not persuasive.
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”) and Lelovas et al. (“The Laboratory Rat as an Animal Model for Osteoporosis Research”, Comp Med. 2008 Oct; 58(5):424-430; hereafter as “Lelovas”), as applied to claims 1 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, Peng and Lelovas teach the elements discussed above.
Yue, Peng and Lelovas 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/Lelovas 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, Lelovas and Guze render the instant claims prima facie obvious.
Response to Arguments
Applicant's arguments, filed June 11, 2026, regarding the 103 rejection over Yue, Peng and Guze have been fully considered but they are not persuasive.
Applicant relies on the same arguments as presented for the 103 rejection over Yue and Peng. No further arguments regarding claim 13, 15 and 16 are presented. Remarks, page 9.
For the same reasons as discussed above, Applicant’s arguments are not persuasive.
New claims 35-37 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”), Chan et al. (US 2017/0360838 A1, Dec. 21, 2017, hereafter as “Chan”) and 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”), as applied to claims 4 and 34 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, Peng, Chan and Hume teach the elements discussed above.
Yue, Peng, Chan and Hume 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/Chan/Hume 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, Chan, Hume and Guze render the instant claims prima facie obvious.
Conclusion
All claims have been 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.
Correspondence
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Casey S. Hagopian
Examiner, Art Unit 1617
/CARLOS A AZPURU/Primary Examiner, Art Unit 1617
Prosecution Insights