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 .
In light of the objections to the claims below, claims 1, 3, 5-6, 8, 13, 17, 20-23, and 31-39 (wherein claims 33-40 have been renumbered as 32-39, respectively), of record 4/12/2024, are pending and subject to prosecution.
Priority
The instant application is a CON of application 16/070202 (US patent 11918687, filed 7/13/2018), which is a national stage entry of PCT/IB2017/000091 (filed 1/13/2017), which claims benefit of provisional application 62/279534 (filed 1/15/2016). Acknowledgement is made of the applicant’s claim for benefit to provisional applications 62/337752 (filed 5/17/2016) and 62/384651 (filed 9/7/2016).
Specification
The use of the terms CryoStor, HypoThermosol, FiberCell, Eudragit, Biomax, Ultracel, and Amicon, which are trade names or marks used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore, the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
The numbering of claims is not in accordance with 37 CFR 1.126 which requires the original numbering of the claims to be preserved throughout the prosecution. When claims are canceled, the remaining claims must not be renumbered. When new claims are presented, they must be numbered consecutively beginning with the number next following the highest numbered claims previously presented (whether entered or not). Misnumbered claims 33-40 have been renumbered 32-39, respectively. Any future responses failing to comply with 37 CFR 1.126 will be held non-responsive and will not be entered.
In claim 31, “and intramuscular injecting” should read “or intramuscular injecting”.
Claim Interpretation
Renumbered claims 33-37 and 39 are interpreted to depend from renumbered claim 32. Renumbered claim 38 is interpreted to depend from renumbered claim 37.
Claims 32 and 39 recite the limitations “wherein the composition comprises exosomes that are at least 20% SDC+” and “wherein the composition comprises exosomes that are at least 50% SDC2+”. These limitations are interpreted as requiring compositions wherein at least 20% or 50% of exosomes are SDC2+.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1, 3, 5, and 8 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more.
Regarding claims 1, 3, and 5: Claims 1, 3, and 5 are directed to compositions comprising isolated exosomes wherein at least 20% or 40% of the exosomes comprise SDC2 or wherein at least 20% of the exosomes comprise SDC2 and the composition does not comprise a living cell. The broadest reasonable interpretation of the exosomes is considered to cover naturally occurring SDC2+ exosomes. Based upon this interpretation, the claims are analyzed as follows:
Step 1: The claims are to a composition of matter, which is a statutory category of invention (Step 1: YES).
Step 2A, prong 1: The claimed compositions comprise SDC2+ exosomes, which are a nature-based product. Sinden et al. teach microparticles or exosomes that comprise SDC2, as determined by proteomic analysis (See table 18). When a claimed composition includes a nature-based product, further analysis is taken to determine if the claimed composition recites a nature-based product judicial exception by comparing the claimed composition to the closest naturally occurring counterpart to determine if the claimed composition has markedly different characteristics than the counterpart.
The closest naturally occurring counterpart of SCD2+ exosomes are naturally occurring SDC2+ exosomes. There is no evidence that the exosomes as claimed differ from SDC2+ exosomes in nature in terms of structural or functional characteristics. The recited percentages of SDC2+ exosomes do not have any effect on their properties in the compositions, nor does their state of isolation with regard to cells or media. The claimed compositions therefore do not have markedly different characteristics from what occurs in nature and are “product of nature” exceptions. Accordingly, the claims are directed to an exception (Step 2A, prong 1: YES).
Step 2A, prong 2: The claims are directed to a product and do not recite any structure that serves to integrate the composition into a practical application (Step 2A, prong 2: NO).
Step 2B: There are no additional elements required by the claims. The claims do not qualify as eligible subject matter and are rejected under 35 U.S.C. 101.
Regarding claim 8: Claim 8 is directed to a composition comprising isolated exosomes wherein at least 20% of the exosomes comprise SDC2 and the composition is frozen. The broadest reasonable interpretation of the exosomes is considered to cover naturally occurring frozen SDC2+ exosomes. Based upon this interpretation, the claim is analyzed as follows:
Step 1: The claim is to a composition of matter, which is a statutory category of invention (Step 1: YES).
Step 2A, prong 1: The claimed composition comprises SDC2+ exosomes, which are a nature-based product. Sinden et al. teach microparticles or exosomes that comprise SDC2, as determined by proteomic analysis (See table 18). Nature-based products can also be frozen, naturally. When a claimed composition includes a nature-based product, further analysis is taken to determine if the claimed composition recites a nature-based product judicial exception by comparing the claimed composition to the closest naturally occurring counterpart to determine if the claimed composition has markedly different characteristics than the counterpart.
The closest naturally occurring counterpart of SCD2+ exosomes are naturally occurring frozen SDC2+ exosomes. There is no evidence that the exosomes as claimed differ from frozen SDC2+ exosomes in nature in terms of structural or functional characteristics. The recited percentage of SDC2+ exosomes does not have any effect on their properties in the composition. The claimed composition therefore does not have markedly different characteristics from what occurs in nature and is a “product of nature” exception. Accordingly, the claim is directed to an exception (Step 2A, prong 1: YES).
Step 2A, prong 2: The claim is directed to a product and does not recite any structure that serves to integrate the composition into a practical application (Step 2A, prong 2: NO).
Step 2B: There are no additional elements required by the claim. The claim does not qualify as eligible subject matter and is rejected under 35 U.S.C. 101.
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.
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, 3, 5-6, 8, 13, 17, 20-23, 31-35, and 37-39 are rejected under 35 U.S.C. 103 as being unpatentable over Elliman (WO 2013117761 A1), of record in IDS dated 1/2/2025, evidenced by Fujisawa et al. (Stem Cells, 2018) and Dreij et al. (Carcinogenesis, 2010), in view of Sinden et al. (WO 2014125277 A1), of record in IDS dated 1/2/2025, and Elliman (WO 2014170411 A1), of record in IDS dated 1/2/2025.
Regarding claims 1, 3, 5, 13, 17, 21-23, 31-32, and 37-39: Elliman ‘761 teaches the therapeutic use of stromal stem cells (which read on “stromal cells”) expressing SDC2 (See Abstract; page 3, 1-2; and page 4, 1). Administration of the cells reduced the inflammatory response in rats following ventilation-induced lung injury (See Example 9). The SDC2+ cells can be used to treat ARDS, COPD, and sepsis (which read on “inflammation response”) (See page 14, 1). The SDC2+ cells can also be used to treat diabetes, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, diabetic cardiomyopathy, and diabetic ulcers (See page 14, 1). Elliman ‘761 does not teach the use of SDC2+ exosomes derived from SDC2+ stromal cells.
Sinden et al. teach the isolation and use of microparticles such as exosomes from conditionally immortalized cells (See Abstract and page 11, line 31-35). The use of microparticles can overcome some of the drawbacks in using cells directly as therapeutic agents (See page 1, line 10-15 and page 2, line 24-27). The microparticle-producing cells can be mesenchymal stem or stromal cells (See page 2, line 11-13 and page 3, line 7-11). The microparticles can comprise SDC2 (See table 18). The microparticles can be purified from conditioned medium by ultracentrifugation or immunoseparation and quantification with antibodies to specific markers (which reads on “the composition does not comprise a living cell”, “culturing the population… in a growth medium, recovering the growth medium…and obtaining an exosome fraction”, and “contacting the growth medium to an… antibody and retaining the exosomes bound”) (See page 32, line 14-36; page 46, line 21-24; and page 53, line 34-37).
Elliman ‘411 teaches that SDC2 demonstrates anti-inflammatory effects in vitro and may be used to treat inflammation and/or inflammatory disease (See page 10, line 20-27 and page 39, line 8-12).
It would have been obvious to one having ordinary skill in the art to modify the methods of Elliman ‘761 to comprise the collection, purification, and therapeutic use of exosomes from SDC2+ cells in place of the cells. One would have been motivated to make this modification because Sinden et al. teach that exosomes overcome some of the drawbacks of using stem cells directly as therapeutic agents (See page 1, line 10-15 and page 2, line 24-27).There would be a reasonable expectation of success in doing so because Sinden et al. teach that exosomes can comprise SDC2 (See table 18) and because they could be easily isolated. While Elliman ‘761 and Sinden et al. do not teach or suggest specific percentages of SDC2+ exosomes, because Elliman ‘411 teaches that SDC2 itself has therapeutic properties (See page 10, line 20-27 and page 39, line 8-12), one of ordinary skill would be reasonably motivated to enrich for optimal levels of SDC2 in the composition that could readily encompass 20%, 30%, 40%, or 50% of the exosomes in the composition comprising this protein, particularly as Sinden et al. teach that microparticles are typically considered to carry a marker if at least about 70% of the exosomes show a detectable level of the marker (See page 17, line 20-23).
Regarding claims 6 and 8: Following the discussion of claims 1, 3, 5, 13, 17, 21-23, 31-32, and 37-39, Elliman ‘761 and Elliman ‘411 do not teach or suggest lyophilization of exosomes, however, Sinden et al. teach that pharmaceutical compositions comprising microparticles can be lyophilized (which reads on “stable for over 48 hours without cryopreservation”) (See page 39, line 12-18).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to further modify the method of Elliman ‘761, modified by Sinden et al. and Elliman ‘411, to comprise lyophilization of the purified microparticles. One would have been motivated to make this modification because Sinden et al. teach that robustness of microparticles confers an advantage over cells in the ability to withstand lyophilization (See page 39, line 15-18), which implies a benefit to this form of dosage. Such a modification could be readily made.
Regarding claim 20: Following the discussion of claims 1, 3, 5, 13, 17, 21-23, 31-32, and 37-39, Elliman ‘761 and Elliman ‘411 do not teach or suggest a composition comprising SCD2+ MSCs and exosomes, however, Sinden et al. teach that the administration of one or more doses of microparticles prior to or concurrent with administration of a stem cell therapy can be used to reduce the risk of rejection of the stem cell therapy (See page 7, line 1-7).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to further modify the method of Elliman ‘761, modified by Sinden et al. and Elliman ‘411, to comprise the inclusion of SDC2+ stem cells in the exosome composition. One would be motivated to make this modification because Sinden et al. teach that concurrent administration can be used to reduce the risk of an adverse immune response to stem cell therapy (See page 7, line 1-7). There would be a reasonable expectation of success in doing so because cells and exosomes could be readily formulated into a single composition for administration.
Regarding claim 31: Following the discussion of claims 1, 3, 5, 13, 17, 21-23, 31-32, and 37-39, Elliman ‘761 and Elliman ‘411 do not teach or suggest injection of exosomes, however, Sinden et al. teach that pharmaceutical compositions comprising the microparticles can be administered by injection and by intravenous, intramuscular, subcutaneous, or intraperitoneal routes (which reads on “intravenous injecting… subcutaneous injecting, intra-peritoneal injecting, and intramuscular injecting”) (See page 39, line 12-15 and page 40, line 17-19).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to further modify the method of Elliman ‘761, modified by Sinden et al., to comprise intravenous, intramuscular, intraperitoneal, or subcutaneous injection. One would have been motivated to make this modification in view of the disease or condition to be treated (See Sinden et al., page 40, line 16-19). There would be a reasonable expectation of success in doing so because Sinden et al. teach that microparticles such as exosomes can be administered by these routes (See page 39, line 12-15 and page 40, line 17-19).
Regarding claims 33-35: Following the discussion of claims 1, 3, 5, 13, 17, 21-23, 31-32, and 37-39, Elliman ‘411 teaches that gamma-irradiation can be used to increase SDC2 expression in the cells via p53 activation (See page 13, line 17-26; page 14, line 12-17; and page 15, line 9-11). Elliman ‘411 also teaches that agents such as desferrioxamine and BPDE can be used to stimulate SDC2 expression (See page 15, line 1-9).
Fujisawa et al. teach that desferrioxamine suppresses proliferation of MSCs without inducing apoptosis (See fig. 1). The teachings of Fujisawa et al. are provided as evidence that desferrioxamine acts a growth arrest agent.
Dreij et al. teach that polycyclic aromatic hydrocarbons (PAH) are carcinogens that activate production of inflammatory mediators and induce chronic inflammation (See page 1149, col. 1, and col. 2, ¶1-2). The PAH BPDE triggers a strong inflammatory response in fibroblasts, in agreement with findings using other cell types (See Abstract; page 1149, col. 2, full ¶2; and page 1156, col. 1, full ¶6). The teachings of Dreij et al. are provided as evidence that BPDE acts as an inflammatory agent.
Claims 1, 3, 5-6, 8, 13, 17, 20-23, and 31-39 are rejected under 35 U.S.C. 103 as being unpatentable over Elliman (WO 2013117761 A1), of record, evidenced by Fujisawa et al. (Stem Cells, 2018) and Dreij et al. (Carcinogenesis, 2010), in view of Sinden et al. (WO 2014125277 A1), of record, and Elliman (WO 2014170411 A1), of record, further in view of Whitford et al. (Genetic Engineering & Biotechnology News, 2015), of record in IDS dated 1/2/2025.
The teachings of Elliman ‘761, Fujisawa et al., Dreij et al., Sinden et al., and Elliman ‘411 are set forth in the rejection above and are incorporated herein in their entirety.
Regarding claim 36: Following the discussion of claims 1, 3, 5-6, 8, 13, 17, 20-23, 31-35, and 37-39, Elliman ‘761, evidenced by Fujisawa et al. and Dreij et al., modified by Sinden et al. and Elliman ‘411 do not expressly teach or suggest the culture of SDC2+ cells in a bioreactor. Sinden et al. teach that microparticles can be produced continuously from conditioned media in a bioreactor, such as a multicompartment bioreactor (See page 29, line 22-30) but do not expressly teach the bioreactor as a hollow fiber bioreactor.
Whitford et al. teach that hollow fiber bioreactors can be used for continuous production of exosomes over periods up to several months and allow for post-confluent cell growth without splitting (See page 2, col. 1, full ¶2-4).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Elliman ‘761, evidenced by Fujisawa et al. and Dreij et al., modified by Sinden et al. and Elliman ‘411, to use a hollow fiber reactor for producing and harvesting exosomes produced from SDC2+ cells. One would be motivated to make this modification because Whitford et al. teach that hollow fiber bioreactors enable efficient and scalable production of exosomes for up to months continuously without requiring splitting of the cells (See page 2, col. 1, full ¶2-4). There would be a reasonable expectation of success in making this modification because SDC2+ cells could be readily cultured in such bioreactors for exosome harvesting.
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, 3, 13, 20-23, 32, and 39 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 4-7 of U.S. Patent No. 11918687. Although the claims at issue are not identical, they are not patentably distinct from each other because of the following reasons.
Regarding claims 1, 3, 13, 17, 32, and 39: Patented claim 1 recites a method of reducing an inflammation response in a mammal comprising delivering a composition comprising SDC2+ exosomes derived from (which reads on “isolating… from”) a population of stromal stem cells to a site of the inflammation response, wherein 20% or more of the population of stromal stem cells are positive for SDC2. The patented claim does not recite a percentage of exosomes comprising SDC2, however, optimization of the percentage of SDC2+ exosomes would be within the power of the ordinary artisan as part of routine experimentation. The patented claim therefore renders obvious the instant claims.
Regarding claim 20: Following the discussion of claims 1, 3, 13, 17, 32, and 39, patented claim 4 recites the method of patented claim 1, wherein the composition further comprises SDC2+ mesenchymal stem cells. The patented claim renders obvious the instant claim.
Regarding claims 21-22: Following the discussion of claims1, 3, 13, 17, 32, and 39, patented claim 5 recites the method of patented claim 1, wherein the inflammation response comprises a diabetic complication. Patented claim 6 recites the method of patented claim 5, wherein the diabetic complication comprises at least one of atherosclerosis, nephropathy, cardiomyopathy, neuropathy, a kidney disorder, kidney failure, a diabetic ulcer, and a leg ulcer. The patented claims render obvious the instant claims.
Regarding claim 23: Following the discussion of claims 1, 3, 13, 17, 32, and 39, patented claim 7 recites the method of patented claim 1, wherein the inflammation response comprises at least one of acute respiratory distress syndrome (ARDS), sepsis, Antisynthetase syndrome, asthma, chronic obstructive pulmonary disease, cystic fibrosis, atelectasis, bronchitis, emphysema, pneumonia, and pulmonary edema. The patented claim renders obvious the instant claim.
Conclusion
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/J.S.S./Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633