DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s amendment and response filed on 12/24/2024 has been received and entered into the case.
Claims 2-3, 12-13 and 18 have been canceled, and claims 1, 4-11, 14-17 and 19-20 have been considered on the merits. All arguments have been considered.
Specification
The disclosure is objected to because of the following informalities: it is noted that the term “relation” in claims 5-6 and 15 has been amended to “relaxation”. The instant specification discloses “relation” instead of “relaxation”, and these typos should be corrected.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 6 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 6 is dependent on claim 1 and discloses that the therapeutically effective amount is about 2x105 cells. The term “about 2x105 cells” of claim 6 does not further limit the range of the amount disclosed in claim 1. Claim 1 discloses 2x105 to 2x106 cells, and “about 2x105 cells” of claim 1 encompasses lower than 2x105 cells. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements. Applicant is advised to delete the term “about”.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1 and 4-10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Gu et al. (2019, BJUI; of record) in view of Sun et al. (2012, Int. J. Androl.; of record) and Ryu et al. (2016, Andrology) as evidenced by Maggi et al. (of record) and Zuliani et al. (of record)
Gu et al. teach a method of treating ED by administering amniotic fluid stem cells (AFSC) in a rat model with pelvic neurovascular injury (Abstract; p.147). The method of Gu et al. resulted in the improvement in the long-term outcomes with neurogenic, myogenic and vascular tissue regeneration in the treatment of NVED (Abstract; p.146, 1st col.). Gu et al. teach that the AFSCs are MSCs positive for CD73, CD105 and negative for CD45 and HLA-DR (p.146, 2nd col., Cell culture).
Regarding the neurogenic erectile dysfunction, the rat model of neurovascular injury causing ED is considered to meet neurological-related problems and neurogenic ED caused by radical pelvic surgeries.
Regarding the therapeutically effective amount being 2x105 to 2x106 cells (claim 1), or about 2x105 cells (claim 6), while Gu et al. teach the amount of the AFSC administered was 2.5x106 cells (Abstract; p.147, 1st col.), they do not teach the identical amount of the claimed limitation.
Sun et al. teach a method of treating ED by injecting 5x105 BM-MSCs to improve erectile function in type-1 diabetic rats (Summary; p.602, 2nd col., last para.).
Ryu et al. teach a method of treating a mouse model of cavernous nerve injury to restore ED by intracavernous delivery of mesenchymal stem cells, and they injected 3x105 cells (Summary; p.174, 2nd col.).
Thus, it would have been obvious to use 3x105 or 5x105 cells for the method of Gu et al. with a reasonable expectation of success.
While Gu et al. in view of Sun et al. and Ryu et al. teach the cell amount within the range of claim 1, however, they do not teach the “about 2x105 cells” (claim 6). However, the amount of 3x105 cells taught by Ryu et al. is considered to fall into the range of “about 2x105 cells”.
Even if the concentration of Ryu et al. is not considered to be within the range of “about” 2x105 cells, however, the teachings of the prior art are close to the claimed range, and thus, it would have been prima facie obvious. MPEP2144.05 states that a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close.
Furthermore, it would have been obvious to a person skilled in the art to adjust the number of cells sufficient to produce a therapeutic outcome in treating erectile dysfunction using the method of Gu et al. A person of ordinary skilled in the art would have been motivated to do so because one skilled in the art would recognize that the amount of cells for a therapeutic treatment is a result-effective parameter, and the concentration of the cells for the method of the cited references would be readily optimized by routine experimentations. M.P.E.P. § 2144.05(II)(A) states that generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical and the normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages. See Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382.
Regarding claim 5 directed to the characteristics of the ED, this limitation does not provide any patentable weight in determining the patentability of the claimed method, and thus, it does not limit the claimed method. Furthermore, as these features are inherent symptoms of the ED, the patients having ED taught by Gu et al. would inherently comprise the claimed feature(s). In support, Maggi et al. teach that smooth muscle relaxation is a key mediator of ED (see Abstract).
Regarding claim 7 directed to the MSC having a fibroblast-like morphology in an attachment culture, this limitation is also considered as inherent to the MSCs. In support, Zuliani et al. teach that AFMSCs adherent on plastic show fibroblast-like morphology (Fig. 2). Thus, it is expected that the AFSCs of Gu et al. have the identical feature.
Regarding claim 8 directed to the differentiation capability of MSCs, the limitation is considered inherent to the MSCs. As AFSCs of Gu et al. are MSCs, they are expected to have identical differentiation capacity as the claimed cells. In support, Zuliani et al. teach that AFMSCs have osteogenic, adipogenic and chondrogenic differentiation (Fig. 3).
Regarding claims 9-10, the wherein clause of the claim is directed to a product-by-process limitation. The process steps of the wherein clause does not provide any other structure than the AF-MSCs being human. Gu et al. teach that the AFSCs are human cells (Abstract; p.146, 2nd col. Materials and Methods).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claim(s) 11, 14-17 and 19-20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Gu et al. (supra) in view of Beaudry et al. (of record), Ichim et al. (supra), Matz et al. (2020, J Tissue Eng Regen Med; of record) and Sun et al. (2012, Int. J. Androl.; of record), as evidenced by Maggi et al. (of record) and Zuliani et al. (of record).
Gu et al. teach a method of treating ED by administering amniotic fluid stem cells (AFSC) in a rat model with pelvic neurovascular injury (Abstract; p.147). The method of Gu et al. resulted in the improvement in the long-term outcomes with neurogenic, myogenic and vascular tissue regeneration in the treatment of NVED (Abstract; p.146, 1st col.). Gu et al. teach that the AFSCs are MSCs positive for CD73, CD105 and negative for CD45 and HLA-DR (p.146, 2nd col., Cell culture).
Regarding the neurogenic erectile dysfunction, the rat model of neurovascular injury causing ED is considered to meet neurological-related problems and neurogenic ED caused by radical pelvic surgeries.
Gu et al. do not teach the use of secretome derived from human AFSCs for the method of treating ED.
Beaudry et al. teach that a therapeutic composition comprising amniotic fluid can be used for treating ED (para. 49), and the therapeutic composition can be acellular amniotic fluid (para. 4).
Ichim et al. teach the use of cell culture supernatant from adipose stem cell or cord blood mesenchymal stem cell for treating ED, and the product to be administered for treating ED can be supernatant of stem cells (para. 32, 63). Ichim et al. also teach amniotic fluid stem cells being used for treating ED (para.65 and 70).
Sun et al. teach that bone marrow-derived mesenchymal stem cell (BM-MSC) and BM-MSCs-conditioned medium, i.e. secretome, provided the beneficial neurotrophic effect in treating erectile dysfunction (see entire document).
Matz et al. teach a method of treating ED by administering conditioned media of human placental stem cells (PSC-CM), and the PSC-CM improves erectile functional recovery and histological structure in a rat model of neurovascular injury-induced ED (Abstract).
It would have been obvious to a person skilled in the art to try the conditioned medium of AFSC, i.e. secretome of AFSC, for treating ED with a reasonable expectation of success. A person of ordinary skilled in the art would have been motivated to do so because Beaudry et al. teach that acellular amniotic fluid can be used in treating ED and various conditioned media from MSCs including BM, PSC, adipose and PSC according to Sun et al., Ichim et al. and Matz et al. can produce therapeutic benefit in treating ED. Therefore, considering various MSCs and their secretome, conditioned media or cell culture supernatant being capable of treating ED, one skilled in the art would reasonably conclude that the conditioned media of AFSC would also produce the similar therapeutic benefit similar to AFSC in treating ED with a reasonable expectation of success.
Regarding the wherein clause of claim 11 directed to the secretome promoting regeneration of a myelin sheath of the subject, this limitation is directed to the results of the claimed method of using secretome. As the combined teachings as discussed above meet the limitation of the claimed method, the results are expected the same.
Regarding claim 14, the rat model of neurovascular injury causing ED taught by Gu et al. is considered to meet neurological-related problems and neurogenic ED caused by radical pelvic surgeries.
Regarding claim 15 directed to the characteristics of the ED, this limitation does not provide any patentable weight in determining the patentability of the claimed method, and thus, it does not limit the claimed method. Furthermore, as these features are inherent symptoms of the ED, the patients having ED taught by Gu et al. would inherently comprise the claimed feature(s). In support, Maggi et al. teach that smooth muscle relaxation is a key mediator of ED (see Abstract).
Regarding claim 16 directed to the therapeutically effective amount of the secretome being 200-2000 mL, Matz et al. teach the CM was collected and concentrated into 2 ml, and 0.2 ml of PSC-CM was injected to the rat (p.1396, 2.5 Intracavernous injection), and Sun et al. teach 200 mL of BM-MSC-conditioned medium was injected (p.602, 2nd col., last para.). Based on these teachings, it would have been obvious to a person skilled in the art to use 0.2 ml (i.e. 200 mL) of conditioned medium, i.e. secretome, obtained from AFSCs with a reasonable expectation of success.
Regarding claim 19 directed to the differentiation capability of MSCs, the limitation is considered inherent to the MSCs. As AFSC of Gu et al. are MSCs, it is expected that the AFSCs of Gu et al. inherently possess the claimed differentiation capabilities. In support, Zuliani et al. teach that AFMSCs have osteogenic, adipogenic and chondrogenic differentiation (Fig. 3).
Regarding claim 20, the wherein clause of the claim is directed to a product-by-process limitation. The process steps of the wherein clause does not provide any other structure than the secretome of AFSCs. As the combined teachings of Gu et al. in view of Beaudry et al., Sun et al., Matz et al. teach that the conditioned medium of AFSCs, the combined teachings would render the subject matter of claim 20 obvious.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Response to Arguments
Applicant’s arguments with respect to the claim rejection under 35 U.S.C. 112(b) have been fully considered and are persuasive based on the instant amendment. The claim rejection has been withdrawn.
Regarding claim rejections under 35 U.S.C. 102 to claims 1-10, applicant’s arguments have been fully considered and are persuasive based on the instant amendment. Therefore, the rejections have been withdrawn. However, a new ground(s) of rejection under 35 U.S.C. 103 is necessitated by the instant amendment as presented above.
Regarding the 103 rejection to claims 1-10 based on Beaudry et al., Ichim et al., Maggi and Zuliani has been withdrawn due to the instant amendment. As discussed above, a new 103 rejection is presented to claims 1 and 4-10.
In the response, applicant argued that the data presented in the specification established a critical and narrow dosage window associated with unexpected peak efficacy. The specification discloses testing several different concentrations of the cells and determined the window of concentration that produces therapeutic efficacy. Upon the teachings of newly cited references, the claimed range (particularly lower end) is considered expected to produce therapeutic efficacy, it is not clear how the data are unexpected. Considering the teachings of prior art, the claimed range of mesenchymal stem cells for treating ED is overlapping with the claimed range or very close to the claimed concentration.
Regarding the 103 rejection to claims 11-20, applicant alleged that the newly added limitation directed to the ED being neurogenic and secretome from AF-MSCs and the secretome promoting regeneration of the myelin sheath would be critical. The Examiner respectfully disagrees with this allegation. There is no evidence that the claimed limitations would be critical particularly the use of secretome (or conditioned medium) of MSCs is known in the art for treating ED caused by cavernous nerve crushing. Applicant’s arguments are focused the outcome/results of the claimed method as the cited references do not particularly disclose the specific results as claimed. However, the patentability of the claimed method would be determined by the active steps to be performed not the results. As the method steps of the combined teachings of the cited references, the results are inherently expected the same. While applicant alleged that the results are “unexpected”, however, there is no evidence to consider that any of the results shown in the instant application is unexpected.
Based on the above discussion, it is the Examiner’s position that the combined teachings of the cited references render the claimed invention obvious.
Conclusion
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.
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/TAEYOON KIM/Primary Examiner, Art Unit 1631