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 .
DETAILED ACTION
Continued Examination under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission of RCE on May 6, 2025 and amendment after final filed on May 6, 2025 has been entered. Claims 3-5, 10, 12-13, 21-34 were canceled, claims 1-2, 6, 8-9, 11 were amended, claim 35 was newly added and claims 1-2, 6-9, 11, 14-20, 35 are pending in the instant application.
The restriction requirement was deemed proper and made FINAL in a previous office action. Claims 11, 14-20, 35 are/remain withdrawn from consideration as being drawn to a non-elected invention/species. Please note that the newly added claim 35 is drawn to a method of use rather than the composition of matter elected for examination. Accordingly, claim 35 is withdrawn from consideration as being drawn to a different invention lacking unity with the elected invention under 37 CFR 1.475(a).
Claims 1-2, 6-9 are examined on the merits of this office action.
Withdrawn Rejections
The rejection of claims 1-2, 5-9 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn in view of amendment of the claims filed May 6, 2025.
The rejection of claim(s) 1-2, 7, 9 under 35 U.S.C. 103 as being unpatentable over Totey (US20150224173 A1) in view of Qiu (Int. J. Mol. Sci. 2016, 17, 1001, pages 1-16, cited previously) as evidenced by Veith (Adv Drug Deliv Rev. 2019 June ; 146: 97–125, cited previously), Victor (WO2014126931), Qiao (Jing Qiao, Na An & Xiangying Ouyang 2017, Platelets) and Hosny (Journal of Blood Transfusion Volume 2015, Article ID 706903, 5 pages) is withdrawn in view of amendment of the claims filed May 6, 2025.
The rejection of claim(s) 1-2, 5-7, 9-10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Totey (US20150224173 A1) in view of Qiu (Int. J. Mol. Sci. 2016, 17, 1001, pages 1-16, cited previously) as evidenced by Veith (Adv Drug Deliv Rev. 2019 June ; 146: 97–125, cited previously), Victor (WO2014126931), Qiao (Jing Qiao, Na An & Xiangying Ouyang 2017 Platelets), Hosny (Journal of Blood Transfusion Volume 2015, Article ID 706903, 5 pages) as applied to claims Claim(s) 1-2, 7, 9 above, in further view of Park* (Molecules 2017, 22, 1259; pages 1-20, cited previously) is withdrawn in view of amendment of the claims filed May 6, 2025.
The rejection of claim(s) 1-2, 7-9 under 35 U.S.C. 103 as being unpatentable over Totey (US20150224173 A1) in view of Qiu (Int. J. Mol. Sci. 2016, 17, 1001, pages 1-16, cited previously) as evidenced by Veith (Adv Drug Deliv Rev. 2019 June ; 146: 97–125, cited previously), Victor (WO2014126931), Qiao (Jing Qiao, Na An & Xiangying Ouyang , 2017 Platelets), Hosny (Journal of Blood Transfusion Volume 2015, Article ID 706903, 5 pages) as applied to Claim(s) 1-2, 7, 9 above, in further view of Banerjee (Int. J. Mol. Sci. 2016, 17, 1001, pages 1-16, cited previously) is withdrawn in view of amendment of the claims filed May 6, 2025.
The rejection of claims 1-2, 6-10 on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 17626882 (reference application) is withdrawn in view of abandonment of copending Application No. 17626882.
The rejection of claims 1-2, 5-10 on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 17626640 (reference application) is withdrawn in view of abandonment of copending Application No. 17626640.
The rejection of claims 1-2, 5-10 on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of co-pending Application No. 17626600 (reference application) is withdrawn in view of abandonment of copending Application No. 17626600.
Maintained/Revised Rejections
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-2, 6-9 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 17626661 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims “A therapeutic composition for treating erectile dysfunction comprising a growth factor concentrate derived from a platelet rich plasma (PRP) and a thermoresponsive polymer, wherein the growth factor concentrate comprises VEGF, EGF, bFGF, IGF-1, PDGF- BB, and TGF-p1, and wherein concentration of the VEGF ranges from 500 to 3000 pg/mL, concentration of the EGF ranges from 100 to 3000 pg/mL, concentration of the bFGF ranges from 25 to 3000 pg/mL, concentration of the IGF-1 ranges from 500 to 3000 ng/mL, concentration of the PDGF-BB ranges from 20 to 3000 ng/mL, and concentration of the TGF-p1 ranges from 100 to 3000 ng/mL (claim 1); derived from convention PRP (Claim 2); comprising peripheral blood stem cells (PBSCs) (claim 1); wherein the PRP or the growth factor concentrate derived therefrom or the PBSCs is autologous or can be derived from umbilical cord blood, bone marrow, fresh/expired platelet concentrates from blood banks, buffy coat from blood banks (Claim 6); an additional therapeutic that is cells and cell secrotome (claim 7); NIPAM based polymer (claim 8); polymer in range of 10-50% (Claim 9) and ratio of 90:10 (claim 10); wherein the ratio of GFC:PBSCs and polymer are 45:45:10 to 5:5:90 (amended claim 1).
Co-pending Application 17/626661 claims A therapeutic composition comprising a platelet rich plasma (PRP) or a growth factor concentrate derived therefrom and a thermoresponsive polymer (see claims 1 and 6) which is identical to the instant claims. Co-pending Application 17/626661 further claims NIPAM based polymer (claim 7); 10-50% polymer (Claim 8); PBSCs (claim 10) at 10-50%; therapeutic agent (claim 11) including cells and secretome; PRP comprises 10-20 fold greater platelet count (see claim 5). Co-pending Application 17/626661 claims “The platelet-derived growth factor concentrate of claim 2, wherein concentration of the VEGF ranges from about 500-1300 pg/mL, concentration of the EGF ranges from about 100-2000 pg/mL, concentration of the bFGF ranges from about 25-500 pg/mL, concentration of the IGF-1 ranges from about 500-1000 ng/mL, concentration of the PDGF-BB ranges from about 20-500 ng/mL, and concentration of the TGF-b1 ranges from about 100-2000 ng/ml” (see claim 3).
Regarding the limitation of “for treating erectile dysfunction” in instant claim 1, Please note that it is regarded that "intended use" of a composition or product will not further limit claims drawn to a composition or product. See, e.g., Ex parte Masham, 2 USPQ2d 1647 (1987) and In Re Hack 114, USPQ 161. A recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim limitation. In the instant case, the combined teachings above teach the same formulation and thus would be capable of the intended use of treating erectile dysfunction.
Co-pending Application 17/626661 does not specifically claim the ratio found in instant claim 1.
However, it would have been obvious before the effective filing date of the claimed invention to optimize the relative proportions of platelet derived growth factor concentrate, PBSCs and thermoresponsive polymer with the ranges recited in the instant claims as a matter of routine optimization.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Applicant’s Arguments
Applicant states “It is respectfully requested that the double patenting rejections be held in abeyance until allowable subject matter is indicated in all claims”. Thus, the rejection is maintained at this time.
Claims 1-2, 6-9 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7, 9-20 of copending Application No. 17626574 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims “A therapeutic composition for treating erectile dysfunction comprising a growth factor concentrate derived from a platelet rich plasma (PRP) and a thermoresponsive polymer, wherein the growth factor concentrate comprises VEGF, EGF, bFGF, IGF-1, PDGF- BB, and TGF-p1, and wherein concentration of the VEGF ranges from 500 to 3000 pg/mL, concentration of the EGF ranges from 100 to 3000 pg/mL, concentration of the bFGF ranges from 25 to 3000 pg/mL, concentration of the IGF-1 ranges from 500 to 3000 ng/mL, concentration of the PDGF-BB ranges from 20 to 3000 ng/mL, and concentration of the TGF-p1 ranges from 100 to 3000 ng/mL (claim 1); derived from convention PRP (Claim 2); comprising peripheral blood stem cells (PBSCs) (claim 1); wherein the PRP or the growth factor concentrate derived therefrom or the PBSCs is autologous or can be derived from umbilical cord blood, bone marrow, fresh/expired platelet concentrates from blood banks, buffy coat from blood banks (Claim 6); an additional therapeutic that is cells and cell secrotome (claim 7); NIPAM based polymer (claim 8); polymer in range of 10-50% (Claim 9) and ratio of 90:10 (claim 10); wherein the ratio of GFC:PBSCs and polymer are 45:45:10 to 5:5:90 (amended claim 1).
Co-pending Application 17626574 claims A therapeutic composition comprising a platelet rich plasma (PRP) or a growth factor concentrate derived therefrom and a thermoresponsive polymer (see claim 1) which is identical to the instant claims. Co-pending Application 17/626574 further claims NIPAM based polymer (claim 10); 10-50% polymer (Claim 11); PBSCs at 10-50% (claim 5); therapeutic agent (claim 7) including cells and secretome (claim 7); PRP comprises 10-20 fold greater platelet count or convention PRP (see claim 2). Co-pending Application 17626574 claims herein concentration of the VEGF ranges from about 500-1300 pg/mL, concentration of the EGF ranges from about 100- 2000 pg/mL, concentration of the bFGF ranges from about 25-500 pg/mL, concentration of the IGF-1 ranges from about 500-1000 ng/mL, concentration of the PDGF-BB ranges from about 20-500 ng/mL, and concentration of the TGF-b 1 ranges from about 100-2000 ng/ml (claim 4).
Regarding the limitation of “for treating erectile dysfunction” in instant claim1, Please note that it is regarded that "intended use" of a composition or product will not further limit claims drawn to a composition or product. See, e.g., Ex parte Masham, 2 USPQ2d 1647 (1987) and In Re Hack 114, USPQ 161. A recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim limitation. In the instant case, the combined teachings above teach the same formulation and thus would be capable of the intended use of treating erectile dysfunction. Co-pending Application 17/626574 does not specifically claim the ratio found in instant claim 1.
However, it would have been obvious before the effective filing date of the claimed invention to optimize the relative proportions of platelet derived growth factor concentrate, PBSCs and thermoresponsive polymer with the ranges recited in the instant claims as a matter of routine optimization.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Applicant’s Arguments
Applicant states “It is respectfully requested that the double patenting rejections be held in abeyance until allowable subject matter is indicated in all claims”. Thus, the rejection is maintained at this time.
New Rejections
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.
Claim(s) 1-2, 6-7, 9 are rejected under 35 U.S.C. 103 as being unpatentable over Totey (US20150224173 A1) in view of Qiu (Int. J. Mol. Sci. 2016, 17, 1001, pages 1-16, cited previously) as evidenced by Veith (Adv Drug Deliv Rev. 2019 June ; 146: 97–125, cited previously), Victor (WO2014126931), Qiao (Jing Qiao, Na An & Xiangying Ouyang 2017, Platelets) and Hosny (Journal of Blood Transfusion Volume 2015, Article ID 706903, 5 pages) Park (Molecules 2017, 22, 1259; pages 1-20, cited previously), Ammar (Saudi Dental Journal, 2018, 30, pages 355-364) and Tan (Biomaterials 30 (2009) 6844–6853) as evidence by Krueger (Stem Cell Translational Medicine, 2018;7:651–663).
Totey teaches a composition comprising a growth factor concentrate derived from human platelets/PRP (see paragraph 0059) for therapeutic use (see abstract) and in particular, treating hair loss (see paragraph 0063, 0077, claim 20) and also in treating wounds (see claim 20). Totey teaches “wherein, the composition is in the form of a cream, gel, aqueous solution, spray-aerosol or transdermal patch” (see claim 26). Totey teaches wherein the composition comprising VEGF (30-300 pg/mL), EGF (900-2000 pg/mL), bFGF (20-100 pg/mL), IGF-1 (paragraph 0064), PDGF-AB(200,000-600,000 pg/ml), PDGF-BB (see paragraph 0064), TGF-B1 (40000-120000 pg/mL) (See paragraph 0037). Totey teaches the GFC displays high propensity towards regeneration or rapid healing of wounds (see paragraph 0064). Totey teaches that “the composition can be in the form of a cream, gel, aqueous solution, spray-aerosol or transdermal patch” (see paragraph 0078). Regarding claim 2, the PRP from which the growth factor concentrate is contained within/derived from is considered conventional PRP (see paragraph 0059). Regarding claim 7, Totey teaches administering the concentrate in addition to blood which would necessarily contain cells and cell secretome.
Totey is silent to including a thermoresponsive polymer, the specific amounts of growth factors (i.e. PDGF-BB and IGF-1) in the formulations, PBSCs and the ratios thereof.
Qiu teaches of a therapeutic composition comprising platelet rich plasma which comprises growth factor concentrate (in absence of any specific definitions of growth factor concentrate) and a thermoresponsive polymer (see abstract, “PDLLA-PEG-PDLLA:PLELand PRP GFs, lines 6-8), the PRP from which the growth factor concentrate is contained within is conventional PRP (see methods, section 4.5). As evidenced by Veith and Qiu, platelet rich plasma contains VEGF, EGF, bGFG, IGF-1, PDGF-BB and TGF-B1 (see page 11, first paragraph, lines 7-9 of Qiu and page 12 of Veith, section 2.4, lines 4-7). Qiu teaches that PRP contains GFs and can heal wounds (see abstract); however, the GFs have short half-life and deactive rapidly therefor a PDLLA-PEG-PDLLA:PLEL gel system with PRP Gfs was utilized. Qiu showed a significantly better ability to raise the number of newly formed blood vessels and faster wound closure (see abstract). Regarding claim 9, the concentration of the polymer is 25 wt % (see section 4.3 of methods). Qiu teaches a final PRP concentration of 10% in the PLEL hydrogel (see section 4.5, 10:90 ratio).
Victor teaches stable PRP compositions in combination with thermoresponsive polymers (see “composition 1”) paragraph 0152, and for treating hair loss and wounds (see claim 79, 76). Victor additionally teaches use of stems cells in combination with the growth factor concentrate (see paragraph 0016, claim 15).
Qiao teaches concentrated growth factor comprising PDGF-BB, TGF-B1, IGF-1 and VEGF which are all naturally comprised in PRP. Qiao teaches varying concentrations including PDGF-BB from approximately 150-200 ng/mL; TGF-b1 at approximately 400-700 ng/mL (figure 2); VEGF up to approximately 300 pg/ml with closer to 350 in PRF (See figure 4); up to 150 pg/mL bFGF (Figure 5) and approximately about 400 ng/mL IgF-1 (see Figure 3).
Hosny teaches VEGF in amount of 600 pg/mL in PRP (see table 3).
Park teaches that “Injection of peripheral blood stem cells enhanced the healing of chronic wounds in horses, which were unresponsive to conventional therapies. Treatment using side-population hematopoietic stem cells, well-characterized self-renewing cells, accelerated wound closure in diabetic mice” (see page 12, second to last paragraph).
Ammar teaches thermoresponsive chitosan B-glycerophosphate hydrogel comprising platelet concentrate and encapsulated stems cells for tissue regeneration (see abstract). The hydrogel released TFG-B1, PDGF-BB and IGF-1 over two weeks (see abstract, results). Ammar teaches that growth concentrate at loadings of 5-15 mg/mL (5-10 vol%) and 90-95% polymer, ratios that overlap the claimed ratios (see page 357, sections 2.3-2.4 and section 2.8). Ammar teaches 150 ul of hydrogel, cells loaded at 10,000 cells (ligament stem cells) per 150 uL (section 2.8), growth concentrate at 5,10, 15 mg/ml (Table 2) and gelation at 37 degrees.
Tan teaches injectable aminated hyaluronic acid G-PNIPAAm (AHA-g-PNIPPAAM) thermoresponsive hydrogels (see abstract). Tan teaches “5 mL of AHA-g-PNIPAAm solution was added into a centrifugal tube containing 25x10^6 ASCs. The final cell density was 5x10^6/mL copolymer solution. Based on an average stem cell diameter of 15-30 uM and volume of 1767-14138 um3 (see evidentiary reference by Krueger et al), Tan teaches encapsulation of adipose derived stems cells with 1-7 weight % cells and 5% polymer solution (which overlaps with the claimed ratio 5:5:90). Tan teaches PNIPAAm-based polymers are routinely used as injectable scaffolds for cell delivery.
It would have been obvious before the effective filing date of the claimed invention to utilize a thermoresponsive polymer/gel in combination with the growth factor concentrate for therapeutic use. One of ordinary skill in the art would have been motivated to do so given the GFs have short half-life and deactivate rapidly therefor a PDLLA-PEG-PDLLA:PLEL gel system with PRP Gfs would be beneficial to improve half-life, stability and improve wound closure. There is a reasonable expectation of success given (1) Totey teaches use in gels for application topically and treating wounds; (2) Qiu and Victor teach use of thermoresponsive polymers for treating wounds and hair loss (Victor) and (3) Ammar teaches the combination of stem cells, growth factor concentrate and temperature sensitive polymer for promoting tissue regeneration via growth factor release.
Regarding the limitation of “for treating erectile dysfunction”, Please note that it is regarded that "intended use" of a composition or product will not further limit claims drawn to a composition or product. See, e.g., Ex parte Masham, 2 USPQ2d 1647 (1987) and In Re Hack 114, USPQ 161. A recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim limitation. In the instant case, the combined teachings above teach the same formulation and thus would be capable of the intended use of treating erectile dysfunction.
Regarding the combination of PBSCs with the wound healing composition of Totey, “It is prima facie obvious to combine two compositions (PRP Growth factors and PBSCs) each of which is taught by the prior art to be useful for the same purpose (treating wounds and healing), in order to form a third composition to be used for the very same purpose…. [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); and Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious). But see In re Geiger, 815 F.2d 686, 2 USPQ2d 1276 (Fed. Cir. 1987) (“Based upon the prior art and the fact that each of the three components of the composition used in the claimed method is conventionally employed in the art for treating cooling water systems, the board held that it would have been prima facie obvious, within the meaning of 35 U.S.C. 103, to employ these components in combination for their known functions and to optimize the amount of each additive….Appellant argues… hindsight reconstruction or at best,… obvious to try’…. We agree with appellant.”). One of ordinary skilled in the art would have been motivated to combine the two each known to be useful for the same purpose, with a reasonable expectation that at least here will be an additive effect.
Furthermore, it would have been obvious before the effective filing date of the claimed invention to include PBSCs into the platelet derived growth factor concentrate of Totey. One of ordinary skill in the art would have been motivated to do so to enhance regenerative efficiency. Totey teaches that PRP growth factors have regenerative properties and help initiate the healing process (see paragraph 0064), while Park demonstrates that PBSCs themselves promote tissue repair. Accordingly, combining PBSCs with Totey’s PRP compositions represents a predictable use of known regenerative components to achieve an additive healing benefit with a reasonable expectation of success.
Regarding claim 1, in particular the ratio of the concentrate, PBSCs and polymer, Qiu teaches a 90:10 ratio of concentrate (active) to polymer (see section 4.5, 10% (v/v); Tan teaches encapsulation of adipose derived stems cells with 1-7 weight % cells and 5% polymer solution (which overlaps with the claimed ratio 5:5:90) and Ammar teaches the combination of polymer, growth concentrate and stem cells.
It would have been obvious before the effective filing date of the claimed invention to optimize the relative proportions of platelet derived growth factor concentrate (including the amounts of each growth factor), PBSCs and thermoresponsive polymer with the ranges/amounts recited in the instant claims as a matter of routine optimization. Qiu teaches combining PRP with a polymer at a 10% v/v PRP loading, demonstrating prolonged growth factor release. Tan teaches a 5wt% polymer and 1vol% stem cells relative to the hydrogel as an injectable scaffold. Ammar teaches the combination of polymer, stem cells and growth factor concentrate to promote tissue regeneration. Together, these references establish that the concentration of each component represents a result effective variable known to affect viscosity, gelation and biological response. Adjusting these amounts to achieve a desired therapeutic consistency or release rate would have been within the level of ordinary skill in the art. One of ordinary skill would have been motivated to vary these ratios through routine optimization to improve handling, injectability, and sustained factor delivery while maintaining cell viability, with a reasonable expectation of success given the predictable nature of thermoresponsive polymer systems. The claimed ratios and amounts of each factor constitute obvious optimization of known art recognized parameters within established ranges for similar compositions (In re Aller, 220 F.2d 454; KSR Int’l Co. v. Teleflex., 550 U.S. 398).
Response to Applicant’s Arguments
Applicant argues that “Example 11 on page 18 of the published Specification describes a study wherein patients with erectile dysfunction were treated with a composition comprising autologous PBSCs and autologous platelet-derived GFC. The results from this study indicate that a single intracavernosal injection of a composition comprising freshly isolated autologous PBSCs and freshly prepared autologous GFC statistically and significantly improved erectile function in the group (paragraph [0234]).
Totey discloses a dosage of an intra-dermally, sub-dermally, intra-articularly or topically administrable growth factor concentrate derived from approximately 1250x106 human platelets per ml, the concentrate comprising approximately 900 to 2000 pg/ml of Epidermal growth factor (EGF), 30 to 300 pg/ml of Vascular Endothelial growth factor(VEGF), 20 to 100 pg/ml of Basic fibroblast growth factor (b-FGF), 40000 to 120000 pg/ml of Transforming growth factor-O (TGF-0) and 200000 to 600000 pg/ml of Platelet Derived growth factor-AB (PDGF-AB) suspended in an isotonic medium (paragraph [0037]). As acknowledged by the Examiner, Totey is silent regarding a thermoresponsive polymer and specific amounts of PDGF-BB and IGF-1 in the formulations.
Additionally, Totey is silent regarding a composition comprising peripheral blood stem cells and the specific ratio of growth factor concentrate, the PBSCs, and thermoresponsive polymer as disclosed by amended Claim 1.
Totey does not teach or suggest "a composition comprising a growth factor concentrate derived from a platelet rich plasma (PRP), a thermoresponsive polymer and peripheral blood stem cells (PBSCs), ... wherein the growth factor concentrate, the PBSCs, and the thermoresponsive polymer are present at a ratio of 45:45:10 to 5:5:90," as recited by amended independent Claim 1.
Qiu, Veith, Victor, Qiao and Hosny do not teach or suggest a composition comprising peripheral blood stem cells (PBSCs) along with a growth factor concentrate derived from a platelet rich plasma (PRP) and a thermoresponsive polymer, in particular a composition wherein the growth factor concentrate, the PBSCs, and the thermoresponsive polymer are present at a ratio of 45:45:10 to 5:5:90, as recited by amended independent Claim 1. Hence, Qiu, Veith, Victor, Qiao and Hosny do not remedy the inadequacies of Totey.
Applicant’s arguments have been fully considered but not found persuasive. Applicant contends that Totey fails to teach or suggest a composition comprising PBSCs, a thermoresponsive polymer or the specific ratio of growth factor concentrate, PBSCs, and polymer as recited in instant claim 1. However, the prior art as a whole (the combination of the references cited in the above rejection, see MPEP 2145 IV) that renders the claimed invention obvious. As discussed above, Totey teaches a therapeutic composition comprising a platelet derived factor growth factor concentrate rich in VEGF, EGF, IGF-1, PDGF-BB, and TGF-B1 for promoting tissue repair and regeneration. Qiu teaches combining PRP growth factors with a thermoresponsve polymer to achieve sustained release and enhanced wound healing, providing a clear motivation to incorporate such hydrogels in compositions like that of Totey to improve retention and delivery at the site of administration. Furthermore, as stated above, it would have been obvious before the effective filing date of the claimed invention to include PBSCs into the platelet derived growth factor concentrate of Totey. One of ordinary skill in the art would have been motivated to do so to enhance regenerative efficiency. Totey teaches that PRP growth factors have regenerative properties and help initiate the healing process (see paragraph 0064), while Park demonstrates that PBSCs themselves promote tissue repair. Accordingly, combining PBSCs with Totey’s PRP compositions represents a predictable use of known regenerative components to achieve an additive healing benefit with a reasonable expectation of success.
Regarding the claimed ratio and amounts of concentrate (including the amount of each growth factor), PBSCs and polymer, Qiu teaches a 90:10 ratio of concentrate (active) to polymer (see section 4.5, 10% (v/v); Tan teaches encapsulation of adipose derived stems cells with 1-7 weight % cells and 5% polymer solution (which overlaps with the claimed ratio 5:5:90) and Ammar teaches the combination of polymer, growth concentrate and stem cells.
It would have been obvious before the effective filing date of the claimed invention to optimize the relative proportions of platelet derived growth factor concentrate (including each growth factor), PBSCs and thermoresponsive polymer with the ranges recited in the instant claims as a matter of routine optimization. Qiu teaches combining PRP with a polymer at a 10% v/v PRP loading, demonstrating prolonged growth factor release. Tan teaches a 5wt% polymer and 1vol% stem cells relative to the hydrogel as an injectable scaffold. Ammar teaches the combination of polymer, stem cells and growth factor concentrate to promote tissue regeneration. Together, these references establish that the concentration of each component represents a result effective variable known to affect viscosity, gelation and biological response. Adjusting these amounts to achieve a desired therapeutic consistency or release rate would have been within the level of ordinary skill in the art. One of ordinary skill would have been motivated to vary these ratios and amounts of each component including the growth factors, through routine optimization to improve handling, injectability, and sustained factor delivery while maintaining cell viability, with a reasonable expectation of success given the predictable nature of thermoresponsive polymer systems. The claimed ratios constitute obvious optimization of known art recognized parameters within established ranges for similar compositions (In re Aller, 220 F.2d 454; KSR Int’l Co. v. Teleflex., 550 U.S. 398).
Accordingly, Applicant’s arguments do not overcome the clear teachings and motivation provided by Totey in view of Qiu, Victor, Qiao, Hosny, Park, Tan and Ammar.
Furthermore, Applicants reliance on Example 11 is not persuasive. Example 11 merely demonstrates that a composition comprising PBSCs and platelet derived GFC produced a therapeutic benefit in a limited patient study. Example 11 fails to demonstrate any criticality or unexpected result (commensurate in scope of the claim) arising from the specific ratio of growth factor, concentrate, PBSCs, and polymer claimed (see MPEP 716.02(d)). Furthermore, the result that GFC/PBSCs would be beneficial in treating erectile dysfunction is not surprising as PRP (which comprises GFC) and stem cells are known to be beneficial in treating erectile dysfunction (see attached handout, Krzastek, published 2018, see pages 3, left column, second to last paragraph, page 6, “PRP section” and page 6, “stem cell therapy”).
Claim(s) 1-2, 6-9 are rejected under 35 U.S.C. 103 as being unpatentable over Totey (US20150224173 A1) in view of Qiu (Int. J. Mol. Sci. 2016, 17, 1001, pages 1-16, cited previously) as evidenced by Veith (Adv Drug Deliv Rev. 2019 June ; 146: 97–125, cited previously), Victor (WO2014126931), Qiao (Jing Qiao, Na An & Xiangying Ouyang 2017, Platelets) and Hosny (Journal of Blood Transfusion Volume 2015, Article ID 706903, 5 pages) Park (Molecules 2017, 22, 1259; pages 1-20, cited previously), Ammar (Saudi Dental Journal, 2018, 30, pages 355-364) and Tan (Biomaterials 30 (2009) 6844–6853) as applied to Claim(s) 1-2, 6-7, 9 above, in further view of Banerjee (Int. J. Mol. Sci. 2016, 17, 1001, pages 1-16, cited previously).
The combined teachings of Totey in view of Qiu, Victor, Qiao, Hosny, Park, Ammar and Tan are described in the above rejection. The combined references are silent to wherein the polymer is NIPAM based polymer.
Banerjee teaches a composition comprising an NIPAAm-co-AAc hydrogel (a thermo responsive polymer) comprising growth factors (meeting the limitations of growth factor concentrate). Banerjee teaches EGF or VEGF both of which are found in platelet rich plasma. Banerjee teaches that NIPAAm-co-AAc hydrogel can be used effectively to deliver growth factors, it is biocompatible and would be beneficial in delivery to wounds (see conclusions, 4).
It would have been obvious before the effective filing date of the claimed invention to utilize the NIPAAm thermoresponsive polymer/gel in combination with the growth factor concentrate for therapeutic use. One of ordinary skill in the art would have been motivated to do so given the GFs have short half-life and deactivate rapidly therefor NIPAAm gel system with PRP Gfs would be beneficial to improve half-life, stability and biocompatible. There is a reasonable expectation of success given Banerjee teaches use for release of growth factors. Regarding the limitation of “wherein the thermoresponsive polymer exists in a liquid form at a temperature ranging from about -20°C to 27°C, and in a gel form at a temperature ranging from about 27.1 °C to 60°C”, these properties are inherent to the NIPAAm polymer gel.
Response to Applicant’s Arguments
Applicants reiterate the aforementioned arguments with respect to the instant rejection. The Office’s rebuttal of these arguments remains the same and is incorporated herein by reference
New Objections
Claim 1 is objected to for the following informality: based on the specification it is unclear that the ratio is based on the weight of each component. Thus, it is suggested Applicant amend the claim to recite “at a w/w ratio of 45:45:10 to 5:5:90”.
Claim 6 is objected to for the following informality: the limitation of “PBSCs is” in line two should be replaced with -PBSCs are-.
Conclusion
No claims are allowed.
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/ERINNE R DABKOWSKI/Examiner, Art Unit 1654