DETAILED ACTION
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 response to restriction requirement filed on June 8, 2026 have been received and entered. Claims 1-68, 79-80, 87 and 88 have been canceled. Claims 69-78 and 81-85 and 86 are pending in the instant application.
Election/Restrictions
Applicant’s election without traverse of claims 68-78. 81-86 (group I) in the reply filed on June 8, 2026 is acknowledged. Applicant’s election of Nrf2 as species for a priming agent in the reply filed on June 8, 2026 is also acknowledged.
Priority
This application is a continuation of PCT/IN2022/050720 filed on 08/11/2022, which claims priority from a foreign application no INDIA 202141036331 on 08/11/2021.
Acknowledgment is made of applicant's claim for a potential foreign priority based on an application 202141036331 filed in India on August 11, 2021. It is noted, however, that applicant has not filed a certified copy of the foreign application IN202141036331 as required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 08/28/2024 and 04/01/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Claims 69-78 and 81-85 and 86 are under consideration.
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.
Claims 81-85 and 86 are rejected under 35 U.S.C. 103 as being unpatentable over Kim (WO2019107939, dated 06/06/2019, IDS), Kuhn (Plastic Reconstr Surg Glob Open 2020, 8(4), 111-112, IDS) and Yamaguchi (J Cell Mol. Med. 2018, 22(2), 1138-1147)/Salehi (Tissue Cell, 2019, 56, 114-120).
Claims are directed to a method of generating a population of primed mesenchymal stem cell-derived exosomes, the method comprising: (a) culturing a population of mesenchymal stem cells (MSCs) in a culture medium;(b) contacting the population of MSCs with an nuclear factor erythroid 2-related factor 2 (Nrf2) activator to obtain a population of primed MSCs;(c) growing the population of the primed MCSs in a collection medium, wherein the collection medium becomes enriched with exosomes produced by the primed MSCs, thereby producing a primed-MSC-derived conditioned medium;(d) collecting the primed MSC-conditioned medium; and(e) purifying the exosomes from the primed MSC-conditioned medium.
With respect to claims 81 and 86, Kim teaches a method of producing a population of primed mesenchymal stem cell-derived exosome, said method comprising culturing a population of mesenchymal stem cells (MSCs) in presence of a priming agent selected from group consisting of pioglitazone, metformin, and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) (see para. 42) to obtain a primed MSC and growing the population of primed MSC in a medium containing FBS (see para. 43), collecting the medium and purifying exosome by centrifuging the medium to obtain exosome derived from primed MSC. It is further disclosed that the culture medium (conditioned) produced from the stem cells could be used for further research ( see para . 44, and 46). It is further disclosed that mesenchymal stem cells are derived from umbilical cord, umbilical cord blood, bone marrow, fat, muscle, nerve, skin, amniotic membrane or placenta (see para. 26). With respect to claim 83, Kim teaches population of MSCs are in contact with the priming agent for about 72 hours (see para. 71).
Kim differs from claimed invention by not disclosing priming agent is NRF2 activator (claim 81), wherein the Nrf2 activator is DMF at a concentration of about 50-100 microM (claims 84-85).
Before the effective filing date of instant application, Kuhn cure the deficiency by disclosing pretreating MSC with potent Nrf2 activator such as CDDO-Im to produce MSC and thereby enhances the exosome yield (see abstract). It is further disclosed that the Nrf2-activated human MSCs increase exosome secretion by 54%, compared to Nrf2-baseline MSCs (p<0.05) (see abstract). The combination of references differs from claimed invention by not disclosing that the Nrf2 activator is DMF.
Yamaguchi teaches Nrf2 activation could be achieved by dimethyl fumarate (DMF). Yamaguchi teaches testing dose response of 1, 10 and 100 micro-M of DMF on cell growth (see figure 1). This is further evidenced by Salehi who reported culturing stem cells at varying confluency at different concentration of DMF (0.1, 1, 10, 25, 50, 75 and 100 micro-M) for varying duration (6h, 24, 72, and 167h) (see 2.3 and 2.4 of pages 115-116, fig. 2, fig. 3).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art to combine the teachings of prior art to modify the method of Kim by substituting one defined priming agent with Nrf activator as disclosed in Kuhn, in a method of producing population of primed mesenchymal stem cell-derived exosome, as instantly claimed, with a reasonable expectation of success, before the effective filing date of instant application. Said modification amounting to combining prior art elements according to known methods to yield predictable results. It would be further obvious for one of ordinary skill in the art to substitute one Nrf2 activator disclosed in Kuhn with another such as DMF disclosed in Yamaguchi/ Salehi. One of ordinary skill in the art would be motivated to do use Nrf2 activator because prior art explicitly reported Nrf2-primed human MSCs increase exosome secretion by 54%, as compared to Nrf2- untreated MSCs (see Kuhn abstract). Other limitation of dosage of Nrf2 activator, confluency of cell and duration of treatment would be an obvious optimization in view of Yamaguchi/Saheli to obtain optimal secretion of exosome without any cytotoxicity. It is well settled that routine optimization is not patentable, even if it results in significant improvements over the prior art. In support of this position, attention is directed to the decision in In re Aller, Lacey, and Haft, 105 USPQ 233 (CCPA 1955): Normally, it is to be expected that a change in temperature, or in concentration, or in both, would be an unpatentable modification. Under some circumstances, however, changes such as these may impart patentability to a process if the particular ranges claimed produce a new and unexpected result which is different in kind and not merely in degree from the results of the prior art. In re Dreyfus, 22 C.C.P.A. (Patents) 830, 73 F.2d 931,24 USPQ 52; ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416, 82 USPQ2d 1385, 1395 (2007) (identifying "the need for caution in granting a patent based on the combination of elements found in the prior art."). One of skill in the art would have been expected to have a reasonable expectation of success in producing exosome from MSC primed with NRf2 activator because prior art successfully reported producing higher number of exosomes from MSC primed with Nrf2 activator as in Kuhn. It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, --USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925.pdf).
Claims 69-77 and 78 are rejected under 35 U.S.C. 103 as being unpatentable over Bhowmick (WO2021009777, dated 1/21/2021)/ Cha et al. (US 20190144830), and further in view of Kim (WO2019107939, dated 06/06/2019, IDS), Kuhn (Plastic Reconstr Surg Glob Open 2020, 8(4), 111-112, IDS) and Yamaguchi (J Cell Mol. Med. 2018, 22(2), 1138-1147)/Salehi (Tissue Cell, 2019, 56, 114-120)
With respect to claims 69, 73, 77, Bhowmick teaches a method of producing mesenchymal stem cells derived exosome, said method comprising: expanding a population of bone marrow derived MSC in culture, containing the population of MSC with corneal stem cell derived conditioned medium (CSSC-CM) to obtain primed MSC (see para, 38, 296-299, example 6), expanding the primed MSC using microcarrier based culture and isolating and purifying exosome from the cell culture (see example 5, para. 261). It is further disclosed that process results in obtaining a stem cell derived-conditioned medium (see claim 2 of ‘777).
With respect to claim 70, Bhowmick teaches culturing BMMSCs in 10 & 25% CSSC-CM supplemented xenofree media till about 90% confluency. Likewise, Cha teaches a method for obtaining an exosome from an expanded primed mesenchymal stem cell population, said method comprising obtaining a population of mesenchymal stem cells (see e.g. paragraphs 0019 and 0024-see e.g. mesenchymal stem cells are human bone marrow or umbilical or adipose or dental in paragraphs 0023 and 0024); culturing the population of mesenchymal stem cells in a culture medium comprising a corneal stromal stem cell derived-conditioned medium (see e.g. paragraph 0024) to obtain primed mesenchymal stem cells (see para. 34-35); expanding the primed mesenchymal stem cells obtained in the cultured medium and expanding performed by either spheroid-based system or a microcarrier-based system (see e.g. paragraph 0035) to obtain the claimed population of expanded primed mesenchymal stem cells (see 59, abstract, claims). Blwomick/Cha differs from claimed invention by not disclosing (i) contacting the population of MSCs with at least one defined Nrf2 priming that is dimethyl fumarate (DMF) or 4 Octyl itaconate (4-0I) for about 12 to about 72 hours (claims 72, 74-76).
Kim cures the deficiency by disclosing a method of producing population of primed mesenchymal stem cell-derived exosome, said method comprising culturing a population of mesenchymal stem cells (MSCs) in presence of a priming agent selected from group consisting of pioglitazone, metformin, and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) (see para. 42) to obtain a primed MSC and growing the population of primed MSC to obtain and purify exosome by centrifuging the medium to obtain exosome derived from primed MSC. The combination of references differs from claimed invention by not disclosing priming agent is a Nrf2 activator that is dimethyl fumarate (DMF).
Before the effective filing date of instant application, Kuhn cure the deficiency by disclosing pretreating MSC with potent Nrf2 activator such as CDDO-Im enhances the exosome yield (see abstract). It is further disclosed that NTA demonstrates that Nrf2-activated human MSCs increase exosome secretion by 54%, compared to Nrf2-baseline MSCs (p<0.05) (see abstract). The combination of references differs from claimed invention by not disclosing that the Nrf2 activator is DMF.
Yamaguchi teaches Nrf2 activation could be achieved by dimethyl fumarate (DMF). Yamaguchi teaches testing dose response of 1, 10 and 100 micro-M of DMF on cell growth (see figure 1). This is further evidenced by Salehi who reported culturing stem cells at varying confluency at different doses of DMF (0.1, 1, 10, 25, 50, 75 and 100 micro-M) for varying duration (6h, 24, 72, and 167h) (see 2.3 and 2.4 of pages 115-116, fig. 2, fig. 3).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art to combine the teachings of prior art to modify the method of Bhowmick/Cha by further contacting MSCs with priming agent as disclosed in Kim or Kuhn, in a method of producing population of primed mesenchymal stem cell-derived exosome, with a reasonable expectation of success, before the effective filing date of instant application. Said modification amounting to combining prior art methods according to known methods to yield predictable results of enhancing exosomes. In the instant case, one of ordinary skill in the art would have been capable of applying this known method of enhancement of MC derived “exosome” by incorporating priming agent as disclosed in Kim/Kihn and the results would have been predictable to one of ordinary skill in the art. It would be further obvious for one of ordinary skill in the art to substitute one Nrf2 activator as disclosed in Kuhn with another such as DMF disclosed in Yamaguchi/ Salehi. One of ordinary skill in the art would be motivated to do so because prior art explicitly reported Nrf2-primed human MSCs increase exosome secretion by 54%, compared to Nrf2- untreated MSCs (see Kuhn abstract). Other limitation of dosage of Nrf2 activator, confluency of cell and duration of treatment would be an obvious optimization in view of Yamaguchi/Saheli to obtain optimal secretion of exosome without any cytotoxicity. It is well settled that routine optimization is not patentable, even if it results in significant improvements over the prior art. In support of this position, attention is directed to the decision in In re Aller, Lacey, and Haft, 105 USPQ 233 (CCPA 1955): Normally, it is to be expected that a change in temperature, or in concentration, or in both, would be an unpatentable modification. Under some circumstances, however, changes such as these may impart patentability to a process if the particular ranges claimed produce a new and unexpected result which is different in kind and not merely in degree from the results of the prior art. In re Dreyfus, 22 C.C.P.A. (Patents) 830, 73 F.2d 931,24 USPQ 52; ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416, 82 USPQ2d 1385, 1395 (2007) (identifying "the need for caution in granting a patent based on the combination of elements found in the prior art."). One of skill in the art would have been expected to have a reasonable expectation of success in producing exosome from MSC primed with conditioned medium and NRf2 activator because prior art successfully reported each produce higher number of exosomes from MSC primed with conditioned medium or Nrf2 activator as in Blowmick and Kuhn. It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, --USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925.pdf).
Claim Rejections - 35 USC § 112-written description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
Claims 69-78 and 81-85 and 86 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims embrace a genus of :
defined priming agent at any dose for any duration to obtain primed MSC.
cell-derived conditioned medium derived from a population of cell different from the population of MSCs to prime MSC.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111 (Fed. Cir. 1991), clearly states that ''applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed.'' Vas-cath Inc. v. Mahurkar, 19USPQ2d at 1 117. The specification does not ''clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.'' Vas-cath Inc. v. Mahurkar, 19USPQ2d at 1116.
The use of at least one defined priming agent and/or cell-derived conditioned medium derived any cell to obtain primed MSC of all the known or yet to be identified defined priming agent and/or cell derived conditioned medium, other than Nrf2 activator, ATRA or SIRT1 activator at concentration of about 50 uM to 100 uM, for 12-24 hours and/or corneal stem cell derived conditioned medium, encompassed within the genus of defined priming agent and/or cell derived conditioned medium (CSSC-CM) have not been disclosed. Based upon the prior art there is expected to be structure variation among the species of defined priming agent and/or cell derived conditioned medium
The specification has provided the description of contacting MSC with corneal stromal stem cell-derived conditioned media(see para. 26, example 1, fig. 1A-1E) and/or Nrf2 activator dimethyl fumarate (DMF), SIRT1 activators, and ATRA at a dose of 50-100 uM for 24 hours to prime MSC to obtain higher yield of exosomes (see fig. 5, 10, 3.12-3.13, para. 202-206)). The specification however has not disclosed genus of other defined priming agent and/or cell-derived conditioned medium derived from any cell to obtain primed MSC to produce enriched population of exosomes as embraced by the claims.
There is no evidence on the record of a relationship between the structures of the Nrf2 activator like DMF and/or CSSC-CM to any of the embraced defined priming agent and/or any cell derived conditioned medium that would provide any reliable information about the structure of defined priming agent and/or cell derived conditioned medium within the genus. There is no evidence on the record that embraced Nrf2 activator such as DMF and/or CSSC-CM had known structural relationships to other defined priming agent and/or any other cell derived conditioned medium; the art indicated that there is variation between structure and/or function of various defined priming agent and/or cell derived conditioned medium. The claimed invention as a whole is not adequately described if the claims require essential or critical feature which are not adequately described in the specification and which is not conventional in the art as of applicants effective filing date. The art teaches seeding density, dose of Nrf2 activator and duration of treatment all play a critical role in priming cell (see section 2.4 and 3.2, Salehi et al Tissue and Cell, 2019, 56, 114-120). Possession may be shown by actual reduction to practice, clear depiction of the invention in a detailed drawing or by describing the invention with sufficient relevant identifying characteristics such that a person skilled in the art would recognize that the inventor had possession of the claimed invention. Pfaff v. Wells Electronics. Inc., 48 USPQ2d 1641, 1646 (1998).
The specification fails to describe what molecules and/cell derived conditioned medium fall into this genus. The skilled artisan cannot envision the detailed chemical structure of the encompassed at least one defined priming agent and/or a cell-derived conditioned medium derived from a population of cells different from the population of MSCs, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993) and Amgen lnc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991).
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 UsPQ2d 1481, 1483. In Fiddes, claims directed to mammalian FGF'S were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
In view of the above considerations one of skill in the art would not recognize that applicant was in possession of the necessary common features or attributes possessed by member of the genus of defined priming agent and/or cell-derived conditioned medium derived any cell to obtain primed MSC, other than the corneal stromal stem cell-derived conditioned media and/or Nrf2 activator dimethyl fumarate (DMF), SIRT1 activators, and ATRA at a dose of 50-100 uM for 24 hours to prime MSC.. Moreover, the art has recognized that there would be variation among the species of the genus of defined priming agent and/cell derived conditioned medium.
Therefore, Applicant was not in possession of the genus of defined priming agent and/or cell-derived conditioned medium derived any cell as encompassed by the claims. University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 held that to fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that ''the inventor invented the claimed invention.''
Conclusion
No claims allowed.
Pandamooz et a (Advanced Biomedical Research, 2014, 1-11) teaches DMF pre-conditioning can enhancer expression of neurotrophic factors in BM-MSC.
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/ANOOP K SINGH/ Primary Examiner, Art Unit 1632
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