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
This action is in response to the papers filed on 07/06/2023. Claims 1-20 are currently pending. Claims 1 is an independent claim.
Therefore, claims 1-20 are examined on their merits to which the following grounds of rejection are applicable.
Priority
Applicant’s claim for the benefit of a prior-filed application filed 7/20/2022 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Thus, the earliest possible priority for the instant application is July 20, 2022.
Specification objection
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892 or an official IDS, they have not been considered.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-20 are rejected 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.
Claim 1 is indefinite in its recitation of the term “cells/aspirate” in lines 2 and 3. The term " cells/aspirate " is not defined by the claim. The specification does not provide any closed definition as to what is meant by “cells/aspirate” and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Appropriate action is required.
Claim 1 is indefinite in its recitation of “a microenvironment that has been altered” as it is unclear as to “the alteration” or alterations that are intended as being encompassed by the noted phrase. Microenvironment are known in the prior art to have numerous alterations, both specific and general. For example, hypoxic microenvironment evokes a spectrum of mild to severe acid-base changes ranging from alkalosis to acidosis. It is suggested that applicant clarify the intended meaning of the noted phrase.
The term “augment the efficacy” in claim 1 is a relative term that render the claim indefinite. The term “augment” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Neither the claim nor the specification sets forth what “augment” is relative to. No standard for comparison is set forth.
Claim 6 and 8-12 recites the phrase “said antioxidant”. There is insufficient antecedent basis for this limitation in the claim. Preceding claims do not mention “antioxidant”.
Claim 7 inherent these deficiencies insofar as they depend from claim 6.
Claim 13 and 14 recites the phrase “said anti-inflammatory agent”. There is insufficient antecedent basis for this limitation in the claim. Preceding claims do not mention “anti-inflammatory agent”.
Claims 15-19 inherent these deficiencies insofar as they depend from claim 14.
Claim 20 is indefinite due to the use of parentheticals. It is not clear whether the parenthetical is used to indicate a limitation, a preferred embodiment, or synonym, etc. Accordingly, the metes and bounds of the claim are not clear.
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.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
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 of carrying out his invention.
Claims 1-20 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.
M.P.E.P. § 2163 recites, “The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see i)(A), above), reduction to drawings (see i)(B), above), or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus (see i)(C), above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.” Further, the written description inquiry is limited to that which is contained within the four corners of the specification, not the extent to which the skilled artisan, given his or her knowledge of the art, would have considered it to expand with only routine experimentation. See Ariad Pharms. Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc); see also id. at 1352 (“[I]t is the specification itself that must demonstrate possession. A description that merely renders the invention obvious does not satisfy the requirement.").
Claims recite a method of treating an ischemic disease in a patient in need comprising administration of bone marrow mononuclear cells/aspirate in a microenvironment that has been altered in order to augment the efficacy of said bone marrow mononuclear cells/aspirate to induce a therapeutic benefit in said ischemic disease with the patient in need. The claims are broadly but reasonably interpreted as administering a bone marrow mononuclear cells/aspirate to treat a genus of ischemic diseases , e.g, Raynaud's disease, peripheral artery disease (PAD), intermittent claudication, vasculitis of small blood vessels, vasospasm, venous thrombosis, venous insufficiency, lymphatic disorders (e.g. lymphatic insufficiency), critical limb ischemia, acute limb ischemia, atheroembolism, and lower extremity ischemia, where the microenvironment that has been altered. There is not structure/ function correlation for the bone marrow mononuclear cells and the genus of microenvironment that has been altered to treat an ischemic disease.
The Specification discloses that a microenvironment that has been altered in order to augment the efficacy of said bone marrow mononuclear cells/aspirate (para. [0005]). In preferred embodiments, the microenvironment has been altered by administration of an antioxidant (para [0010]). The Specification contemplates administration of zinc, ubiquinol, argon gas, neon gas, selenium, vitamins C and E, n-acetylcysteine and others as antioxidants (para [0017]-[0042]; [0157]; [0159]). The Specification also contemplates alteration by administration of a complement inhibitor prior to, concurrent with, and subsequent to administration of said bone marrow cells (para [0107]). However, the specification is silent about any in vivo example where bone marrow mononuclear cells are administered together with said genus of antioxidants or inhibitors to augment a desired biological property of the bone marrow mononuclear cells in the treatment of ischemic conditions.
The prior art of Marbán et al (JAMA, 2012) teaches that use of bone marrow derived cell therapy for ischemic heart disease leads to mixed results. Studies have indicated that benefit from bone marrow cell therapies is variable based on ischemic disease, for instance there was no significant incremental treatment effects on function, volumes, or infarct size in patients treated with bone mononuclear cells (page 1, column 1 and 2). Ma et al (Int J Mol Sci., 2025) teaches that although clinical trials have initially demonstrated the potential of bone marrow cells to improve tissue repair and function, they have also revealed challenges related to cell survival, delivery efficiency, standardization, and therapeutic consistency (section 7. Conclusions, page 17).
The specification does not identify disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. Rather, in the instant application, the specification invites the skilled artisan to test each and every microenvironment that has been altered in order to augment the efficacy of said bone marrow mononuclear cells/aspirate.
Further, the prior art shows that attempts to treat various ischemic diseases using bone marrow mononuclear cells have been unsuccessful as each organ requires different routes of administration, concentration of cells, addition of augmenting agents, etc. In this case, the skilled artisan would not have reasonably concluded at the time of the invention that applicant was in possession of the invention as claimed. Any claim not specifically recited is included in the rejection because it depends from a rejected claim.
Lack of Enablement
Claims 1-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification does not reasonably provide enablement for treating ischemic disease by administering bone marrow mononuclear cells/aspirate in a microenvironment that has been altered in order to augment the efficacy of cells to induce a therapeutic benefit. The claim contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with the claim.
breadth of the claim; nature of the invention
The claim is broad, encompassing treating a patient in need with any kind of ischemic disease, e.g, Raynaud's disease, peripheral artery disease (PAD), intermittent claudication, vasculitis of small blood vessels, vasospasm, venous thrombosis, venous insufficiency, lymphatic disorders (e.g. lymphatic insufficiency), critical limb ischemia, acute limb ischemia, atheroembolism, and lower extremity ischemia (para [0136] of the published application) by administering bone marrow mononuclear cells/aspirate to any microenvironment that has been altered by a genus of agents , e.g, antioxidants or inhibitors that augments the efficacy of the cells and leads to an undefined therapeutic benefit in the patient. Thus, the claims are drawn to a large genus of ischemic diseases, microenvironments, (e.g, articular niche), levels of efficacy of the cells, and levels of therapeutic benefit to the patient.
the amount of direction provided by the inventor; the existence of working examples:
However, the specification does not disclose a reduction to practice in the method of treating ischemic disease patients by using enhanced bone marrow mononuclear cells/aspirate. There are no working examples of using this method for treatment of any ischemic disease patient, let alone indication of success in using this method. Thus, the specification does not provide sufficient teachings for the enablement of treating ischemic disease.
the state of the prior art; the level of predictability in the art:
The prior art of Marbán et al (JAMA, 2012) teaches that use of bone marrow derived cell therapy for ischemic heart disease leads to mixed results. Studies have indicated that benefit from bone marrow cell therapies is variable based on ischemic disease, for instance there was no significant incremental treatment effects on function, volumes, or infarct size in patients treated with bone mononuclear cells (page 1, column 1 and 2). Ma et al (Int J Mol Sci., 2025) teaches that although clinical trials have initially demonstrated the potential of bone marrow cells to improve tissue repair and function, they have also revealed challenges related to cell survival, delivery efficiency, standardization, and therapeutic consistency (section 7. Conclusions, page 17). Moreover, optimizing the dosage is critical, as studies show a wide range of infusion doses are needed to elicit therapeutic benefit (page 12). Alves et al (Tissue Eng Part A., 2013) teaches that hMSCs can accumulate high amounts of oxidative damage and that the observed preventive effect of antioxidant supplementation was unable to fully prevent the accumulation of oxidative damage, ultimately leading to the loss of differentiation potential (i.e. regenerative capacity) and render these cells less optimal for clinical usage (page 8, column 2). Furthermore, Ching-Chuan va Rhijn-Brouwer et al (STEM CELLS AND DEVELOPMENT, 2022) demonstrated that human bone marrow mononuclear cells do not improve limb perfusion when injected intramuscularly (i.e. within the microenvironment) (page 1, abstract) while Pokushalov et al (J. of Cardiovasc. Trans. Res., 2010) demonstrated that intramyocardial injections (i.e. within the microenvironment) of autologous bone marrow mononuclear cells in patients with ischemic heart failure showed improved survival, clinical symptoms, and beneficial effect on left ventricular function (page 1, abstract). Thus, it is unpredictable if administration of bone marrow mononuclear cells would lead to success when used on different ischemic diseases or organs.
Therefore, the prior art discloses that bone marrow mononuclear cells could potentially provide benefit to ischemic disease patients. However, the prior art provides no specific guidance for treating specific ischemic diseases and conditions claimed and sets forth that attempts to treat various ischemic diseases using bone marrow mononuclear cells have been unsuccessful as each organ requires different routes of administration, concentration of cells, addition of augmenting agents, etc. Therefore, the amount of experimentation required to practice the invention as broadly claimed would not be reasonable.
the quantity of experimentation needed to make or use the invention based on the content of the disclosure:
The skilled artisan would be required to perform under levels of experimentation in order to practice the claimed invention. The instant specification does not reduce to practice the claimed invention; the instant specification does not provide guidance on how to reasonably predict which patient is in need, which route of administration to use for the bone mononuclear cells, how to gauge the microenvironment in need of administration of cells, what agents to use prior to, concurrent with, and subsequent to administration of said bone marrow cells to augment the efficacy of said bone marrow mononuclear cells/aspirate, what the alteration to the microenvironment is and level of augmentation of efficacy of cells. Thus, the skilled artisan would be forced to 1) determine ischemic patient in need and 2) determine microenvironment needing administration of cells and 3) determine the level of augmentation of efficacy, and 4) determine level of therapeutic benefit elicited by the cells to the patient in need.
the level of one of ordinary skill:
The level of one of ordinary skill is a PhD holder.
Conclusion
When all of the Wands factors are considered together, they establish a prima facie case that the specification is not enabling for the claims. While a lack of a working embodiment cannot be a sole factor in determining enablement, the lack of any working examples, in light of the unpredictable nature of the art and the lack of direction applicants present, provides additional weight to the lack of enablement in consideration of the Wands factors as a whole. Thus, one of ordinary skill in the art would not have had a reasonable expectation of success in making or using the claimed invention.
Provisional Rejection, Obviousness Type Double Patenting-No secondary Reference(s)
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 1-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 18,358, 490 as per claims filed on 7/25/2023. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are obvious over the cited claims of Application 18,358,490.
Claim 1 of copending application no.18,358, 490 is directed to a method of augmenting regenerative activity of a bone marrow mononuclear cell /aspirate preparation comprising the steps of: a) obtaining a bone marrow mononuclear cell population /aspirate; b) administering said bone marrow mononuclear cell population /aspirate into a subject; and c) administering a concentration of oxytocin into said subject at a concentration and capable of augmenting said regenerative activity of said bone marrow mononuclear cell population /aspirate.
Claims 5-6 of copending application require that augmenting regenerative activity comprises protection of cells from apoptosis caused by ischemic conditions.
Claim 1 of the invention is directed to a method of treating an ischemic disease in a patient in need comprising administration of bone marrow mononuclear cells/aspirate in a microenvironment that has been altered in order to augment the efficacy of said bone marrow mononuclear cells/aspirate to induce a therapeutic benefit in said ischemic disease with the patient in need.
Claim 1 of the instant application is drawn to a broad genus of augmenting regenerative activity and requires the step of altering a microenvironment. Claim of 1 of 18,358, 490 requires administration of oxytocin into said subject to alter a microenvironment. Said methods of administration comprising oxytocin are members of the claimed genus of the instant claim 1. It is well established that a species of a claimed invention renders the genus obvious. In re Schaumann , 572 F.2d 312, 197.
This is a provisional obviousness-type double patenting rejection because the conflicting claims have not in fact been patented.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Juliana Candelaria whose telephone number is (571)272-5488. The examiner can normally be reached Monday - Friday 8am - 5pm.
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/JULIANA IRENE CANDELARIA/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634