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 .
Election/Restrictions
Applicant’s election of Group 7 in the reply filed on 12/1/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Upon reconsideration, the restriction requirement between Groups 1-9 is withdrawn. Furthermore, all election of species requirements are withdrawn. Applicants may re-present claims to embodiments of claim 1 that were drawn to any of original Groups 1-6 and/or 8-9.
Claims 1, 5, 6, 8, 10 and 14 read on the elected invention, all have been considered on the merits.
Priority
The instant application is a national stage entry of PCT/US2021/070638, filed 5/28/2021. Acknowledgement is made of Applicants’ claim for benefit to prior-filed US Provisional application 63/031782 (filed 5/29/2020).
Claim Objections
Claims 8, 10 and 14 are objected to for minor informalities: A “condition” is not administerable to a subject. Claim 8 is understood to require the method of claim 1 to further comprise: i) administration of one or more additional therapeutic agents to the individual in need thereof in combination with the fibroblast cell population, and/or
ii) subjecting the individual in need thereof to one or more therapeutic conditions.
Claim Interpretation
The sole independent claim is directed to a method of inhibiting blood vessel degeneration in an individual in need thereof.
It is necessary to determine the patient population covered by ‘individuals in need [of inhibiting of blood vessel degradation]’. Blood vessel degradation is defined by the specification as “the initiation and progression of various pathological processes which contribute to the development of blood vessel disorders, including weakening of the blood vessels and aneurysm formation” (See paragraph 0035 of as-filed specification). This broad definition includes, but is not limited to, damage to or dysfunction of any of the layers of blood vessels (i.e. damage or degradation of the endothelium, tunica intima, and/or the adventitia), aneurysms and aortic dissection. The specification identifies that endothelial dysfunction occurs as a natural part of aging (See paragraph 0006 of as-filed specification). As the claim recites patients in need of inhibition of blood vessel degradation, the scope will cover healthy patients, as everyone is in need of inhibition of degradation of blood vessels, e.g. inhibition of aneurysms, aortic dissections, or even endothelial dysfunction as a result of aging. Therefore, the scope of “individuals in need of inhibiting blood vessel degeneration” include everyone, including, but not limited to, healthy subjects.
The method of the independent claim requires administration of an effective amount of a composition comprising (i) a fibroblast cell population, (ii) fibroblast-derived products, and/or (iii) conditioned media from the (i) fibroblast cell population and/or (ii) fibroblast-derived products. (ii) Fibroblast-derived products are defined at paragraph 0043 as covering molecular or cellular agents derived or obtained from one or more fibroblasts. This will cover conditioned media, extracellular vesicles, nucleic acids, proteins, lipids, and any other cellular component. The specification also states that cells differentiated/de-differentiated from fibroblasts, such as stem cells, are included in the scope of ‘fibroblast-derived products’ (See paragraph 0043).
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 5 and 8 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by O’Heeron (WO 19/125996), evidenced by Fang et al (Tissue and Cell, 2017).
O’Heeron disclose methods of enhancing a therapeutic activity of a fibroblast, comprising providing to the fibroblast an effective amount of one or more agents and/or one or more conditions that comprise stimulation of native heme oxygenase (HO)-1 expression in the fibroblasts, exposure of the fibroblasts to exogenously provided HO-1, and/or expression of HO-1 from an exogenously provided vector in the fibroblasts (See para 0005). O’Heeron further disclose providing an effective amount of the fibroblasts and/or a conditioned medium therefrom to an individual in need thereof. The individual may have an autoimmune disease, a degenerative disease, an inflammatory diseases, and/or a fibrotic disease (See para 0006).
Regarding claim 1: The step of administering a therapeutically effective amount of fibroblasts and/or conditioned medium therefrom to a subject having an autoimmune disease, a degenerative disease, an inflammatory diseases, and/or a fibrotic disease reads on the sole active step of claim 1. For the reasons discussed under Claim Interpretation, everyone is in need of inhibition of blood vessel degeneration. Thus, subjects having an autoimmune disease, a degenerative disease, an inflammatory diseases, and/or a fibrotic disease are each considered individuals in need of inhibiting blood vessel degeneration. By administering fibroblasts and/or conditioned medium thereof, O’Heeron inherently inhibits blood vessel degeneration. This conclusion is based on the principle of inherency: O’Heeron carries out the same active step on the same patient population as the claims, thus the resulting effect will also be the same as that claimed.
Regarding claim 5: O’Heeron disclose use of foreskin fibroblasts (See para 0052). Fang et al is cited to evidence that foreskin fibroblasts are CD73+ (See Fang et al, abstract, as well as “4.3. Immunophenotype of dermal fibroblasts…”).
Regarding claim 8: O’Heeron teach additional therapeutic agents can be administered along with the fibroblast-conditioned medium, including, inter alia… immunosuppressant agents (See para 0032). This reads on one or more additional therapeutic agents.
Claims 1, 5, 8, 10 and 14 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by O’Heeron et al (WO 20/093051).
O’Heeron et al disclose treatment or prevention of brain injury, comprising administration of a therapeutically effective amount of fibroblasts (See para 0013). The brain injury can be traumatic brain injury, or hemorrhagic stroke (See para 0015).
Regarding claim 1: The step of administering a therapeutically effective amount of fibroblasts to a subject having, or at risk of having a brain injury, reads on the sole active step of claim 1. For the reasons discussed under Claim Interpretation, everyone is in need of inhibition of blood vessel degeneration. Thus, subjects having, or at risk of having, a brain injury read on individuals in need of inhibiting blood vessel degeneration. By administering fibroblasts, O’Heeron inherently inhibits blood vessel degeneration. This conclusion is based on the principle of inherency: O’Heeron carries out the same active step on the same patient population as the claims, thus the resulting effect will also be the same as that claimed.
Regarding claim 5:O’Heeron et al teach the administered fibroblasts are CD56 and/or CD73+ (See para 0032).
Regarding claim 8: O’Heeron et al teach the method can further comprise an additional therapy for brain injury or stroke. The additional therapy can include, inter alia, administration of at least one additional therapeutic agent and/or at least one medical procedure or supportive therapy (See para 0022). The additional medical procedure and/or supportive therapy read on conditions.
Regarding claim 10: Following the discussion of claim 8 above, the additional therapeutic agent can be, inter alia, an immunomodulatory agent, such as VEGF.
Regarding claims 10 and 14: Following the discussion of claim 8 above, the additional supportive therapy can physical therapy (See para 0074), which reads on exercise. Applicants state exercise will serve to mobilize endothelial progenitor cells.
Claims 1, 5, 8 and 10 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by O’Heeron (WO 21/097423).
O’Heeron et al disclose a method of treating or preventing a stroke comprising providing to the subject an effective amount of fibroblasts or exosomes from the fibroblasts (See para 0012).
Regarding claim 1: The step of administering a therapeutically effective amount of fibroblasts or fibroblast-derived exosomes to a subject having, or at risk of having a stroke reads on the sole active step of claim 1. For the reasons discussed under Claim Interpretation, everyone is in need of inhibition of blood vessel degeneration. Thus, subjects having, or at risk of having, a stroke read on individuals in need of inhibiting blood vessel degeneration. By administering fibroblasts or exosomes from fibroblasts, O’Heeron inherently inhibits blood vessel degeneration. This conclusion is based on the principle of inherency: O’Heeron carries out the same active step on the same patient population as the claims, thus the resulting effect will also be the same as that claimed.
Regarding claim 5: O’Heeron et al disclose the fibroblasts can be adult bronchial fibroblasts, which are CD73+ (See para 0088). Regarding claims 8 and 10: O’Heeron et al teach the method can further comprise providing an additional agent to the subject, wherein the additional agent can comprise, inter alia VEGF (see para 0019).
Claims 1, 6, 8, 10 and 14 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Riordan et al (US 2009/0291061), evidenced by Christiansen-Weber et al (US 2015/0299660).
Riordan et al disclose methods of inhibiting and/or reversing blood vessel degeneration comprising administering a therapeutically effective amount of a stem cell population to a degenerated blood vessel population (See para 0012). Specifically, the method can be applied to treat an aneurysm in a patient (See para 0022). The stem cell population can comprise, inter alia, mesenchymal stem cells (See para. 0014).
Regarding claims 1 and 6: The method of Riordan et al inhibits blood vessel degeneration. Mesenchymal stem cells are capable of being derived from fibroblasts (See Christiansen-Weber et al, para 0099, Ex 4). Thus mesenchymal stem cells read on fibroblast-derived products. Administration of a therapeutically effective amount of mesenchymal stem cells (fibroblast-derived products) to a patient with an aneurysm is squarely within the scope of the claims.
Regarding claim 8: Riordan et al teaches that additional pharmaceutical agents can be administered (See para 0013). These read on additional therapeutic agents.
Regarding claim 10: Following the discussion of claim 8 above, Riordan et al teach the pharmaceutical agent can comprise, inter alia, matrix metalloproteinases. Additional claimed agents are taught at paragraphs 0015-0017.
Regarding claims 8, 10 and 14: Riordan et al teaches the therapy can further comprise conditions effective to mobilize endothelial progenitor cells. Said conditions effective to achieve mobilization include, inter alia, exercise, hyperbaric oxygen, and the other conditions recited in claim 14 (See para 0015-0018).
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 1, 5, 6, 8, 10 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Riordan et al (US 2009/0291061), in view of Ichim et al (J Transl Med, 2018).
The teachings of Riordan et al are set forth above. Briefly, Riordan et al discloses inhibiting of blood vessel degradation by administration of a therapeutically effective amount of stem cells, specifically mesenchymal stem cells (MSCs).
Riordan et al does not teach inhibition of blood vessel degradation by administration of fibroblasts.
Ichim et al discloses fibroblasts as a practical alternative to MSCs in therapeutic uses (See title). Ichim et al identifies several drawbacks to obtaining and using MSCs, including invasive harvesting procedures, scarcity of the cells requiring significant in vitro expansion which introduces opportunity for mutagenesis, and required isolation from heterogenous populations (See abstract and Pg 2, col. 1). Ichim et al states fibroblasts avoid these drawbacks, as they are readily available from easily accessible biopsy samples in large numbers, do not require as extensive isolation and in vitro expansion, and have shorter doubling times (See id). Ichim et al note parallel phenotypic and functional characteristics of MSCs and fibroblasts, including differentiation capability, immune modulation and regenerative properties (See abstract). Ichim et al set forth the concept that fibroblasts may be used as a practical alternative, and potentially more effective cell therapy than MSCs (See abstract).
Regarding claims 1, 6, 8, 10 and 14: Based on the comments by Ichim et al, one having ordinary skill in the art would have had a reasonable expectation that fibroblasts could be substituted for the MSCs in the method of Riordan et al. In making the substitution, one would carry out the method of Riordan et al, specifically administering fibroblasts to inhibit blood vessel degeneration in an individual with at least one aneurysm. The additional agents and conditions taught by Riordan et al (reading on claims 8, 10 and 14) remaining the same. This conclusion of obviousness is based on the substitution rationale. One would have had a reasonable expectation of successfully making the substitution based on the teachings of Ichim et al. Regarding claim 5: Ichim et al teach dermal foreskin fibroblasts as an appropriate fibroblast source. Dermal foreskin fibroblasts are CD73+ (see Ichim et al, Pg 3, 2nd col).
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, 5, 8, 10 and 14 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-32 of U.S. Patent No. 12310991, optionally further in view of Fang et al (Tissue and Cell, 2017), and/or Riordan et al (US 2009/0291061).
Although the claims at issue are not identical, they are not patentably distinct from each other because the patented claims anticipate and/or render obvious the instant claims as follows:
Regarding claim 1: Patented claim 1 recites a method of stimulating angiogenesis in an individual, comprising administering an effective amount of fibroblast-derived exosomes. Patented claims 31 and 32 define the individual as one at risk of limb loss, having ischemic heart disease, ischemic brain disease, in need of wound repair and/or having diabetes. All of these individuals are in need of inhibition of blood vessel degeneration. The fibroblast-derived exosomes read on a fibroblast-derived product. By administering fibroblast-derived exosomes, the patented method will inherently inhibits blood vessel degeneration. This conclusion is based on the principle of inherency: the patented method carries out the same active step on the same patient population as the claims, thus the resulting effect will also be the same as that claimed.
Regarding claim 5: At the time the application was filed, dermal foreskin fibroblasts were a well-known and common source of fibroblasts (See, e.g. Fang et al). As such it would have been prima facie obvious to have used dermal foreskin fibroblasts as the fibroblast source. Fang evidences that dermal foreskin fibroblasts are CD73+ (See Fang , Pg 58, “4.2. Immunofluorescence staining…”).
Regarding claims 8, 10 and 14: The patented claims do not teach administering additional agents or ‘conditions’ that would further aid in angiogenesis. Riordan eta l (teachings set forth above) teach a variety of therapeutic agents and conditions that serve to enhance blood vessel regeneration, including each of those agents and conditions of claims 8, 10 and 14. Given that both the patented claims and the therapeutic agents and/or conditions of Riordan et al aim to regenerate blood vessels, it would have been prima facie obvious to have combined the therapies to administer both the exosomes and the therapeutic agents and/or conditions of Riordan et al. In combining the therapies one would have had a reasonable expectation of at least additive results. This conclusion of obviousness is based on combining known equivalents rationale.
Claims 1, 5, 8, 10 and 14 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over:
Claims 1-3, 5, 8, 9-13, 16-28 of copending US application 17/309178
Claims 1-7 and 22 of copending US application 17/309207
Claims 1, 3, 13, 14, , 19-26, 28-35, 37, 42-43, 49-52, 58-59, 69-82 of copending US application 17/755837
Claims 1-30 of copending US application 19/331852
Claims 1-4, 6-10, 12-16, 20, 23, 24, 28-31 of copending US application 18/184726
Claims 15-31 of copending US application 18/433831,
each optionally further in view of Fang et al (Tissue and Cell, 2017), and/or Riordan et al (US 2009/0291061).
Although the claims at issue are not identical, they are not patentably distinct from each other because the copending claims anticipate and/or render obvious the instant claims as follows:
Regarding claim 1: Each set of copending claims includes an independent claim that recites a method involving administration of fibroblast cells, fibroblast conditioned medium and/or fibroblast-derived exosomes. The methods are administered to subjects who have had, or are at risk of having, strokes and/or have wounds. Subjects who have had, or are at risk of having strokes, as well as subjects with wounds, are all in need of inhibition of degeneration blood vessels. By administering the fibroblast, conditoined medium and/or fibroblast-derived exosomes, the copending methdos will inherently inhibits blood vessel degeneration. This conclusion is based on the principle of inherency: the copending methods carries out the same active step on the same patient population as the claims, thus the resulting effect will also be the same as that claimed.
Regarding claim 5: At the time the application was filed, dermal foreskin fibroblasts were a well-known and common source of fibroblasts (See, e.g. Fang et al). As such it would have been prima facie obvious to have used dermal foreskin fibroblasts as the fibroblast source. Fang evidences that dermal foreskin fibroblasts are CD73+ (See Fang , Pg 58, “4.2. Immunofluorescence staining…”).
Regarding claims 8, 10 and 14: The copending claims do not teach administering additional agents or ‘conditions’ that would further aid in angiogenesis. Riordan eta l (teachings set forth above) teach a variety of therapeutic agents and conditions that serve to enhance blood vessel regeneration, including each of those agents and conditions of claims 8, 10 and 14. Given that both the copending claims and the therapeutic agents and/or conditions of Riordan et al aim to regenerate blood vessels, it would have been prima facie obvious to have combined the therapies to administer both the exosomes and the therapeutic agents and/or conditions of Riordan et al. In combining the therapies one would have had a reasonable expectation of at least additive results. This conclusion of obviousness is based on combining known equivalents rationale.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALLISON M FOX whose telephone number is (571)272-2936. The examiner can normally be reached M-F 10-6 EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Christopher Babic can be reached at 571-272-8507. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ALLISON M FOX/Primary Examiner, Art Unit 1633