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 October 8, 2024.
Claim Amendments
The instant claims are the original claims filed on 10/08/2024.
Claims 1-20 are pending and under examination.
Priority
The instant application 18/909,327 was filed on 10/08/2024. This application is a continuation (CON) of international application PCT/IL2024/050706 filed 07/18/2024, a CON and a continuation-in-part (CIP) of U.S. Application No. 18/474,676 filed 09/26/2023 (now, U.S. Patent No. 12,115,196), and claims priority based on U.S. Provisional Application No. 63/514,580 filed 07/20/2023.
Noncompliance with 35 U.S.C. 102:
MPEP 211.05 instructs:
The disclosure of a continuation application must be the same as the disclosure of the prior-filed application; i.e., the continuation must not include anything which would constitute new matter if inserted in the original application. See MPEP § 201.07. The disclosure of a divisional application must be the same as the disclosure of the prior-filed application, or include at least that portion of the disclosure of the prior-filed application that is germane to the invention claimed in the divisional application. See MPEP § 201.06. The disclosure of a continuation or divisional application cannot include anything which would constitute new matter if inserted in the prior-filed application. A continuation-in-part application may include matter not disclosed in the prior-filed application. See MPEP § 201.08. Only the claims of the continuation-in-part application that are disclosed in the manner provided by 35 U.S.C. 112(a) in the prior-filed application are entitled to the benefit of the filing date of the prior-filed application. If there is a continuous chain of copending nonprovisional applications, each copending application must disclose the claimed invention of the later-filed application in the manner provided by 35 U.S.C. 112(a) in order for the later-filed application to be entitled to the benefit of the earliest filing date.
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 120 as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or earlier-filed nonprovisional application or provisional application for which benefit is claimed). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
In this case, applicants claims the instant application 18/909,327 is a CON of both international application PCT/IL2024/050706 and U.S. Application No. 18/474,676. However, the disclosure of present application 18/909,327 contains subject matter which was not originally described in international application PCT/IL2024/050706 and U.S. Application No. 18/474,676, e.g., Examples 3-6 and additional paragraphs/sentences throughout the specification.
Accordingly, the additional subject matter found in the instant application is not sufficiently supported or enabled by the prior-filed application, U.S. Application No. 16/105,319, in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph. In sum, the subject matter added to the disclosure of the instant application would “constitute new matter if inserted in the prior-filed application” (MPEP 211.05).
Applicant states that the instant application is a CON of the prior-filed applications, international application PCT/IL2024/050706 and U.S. Application No. 18/474,676. For the reasons provided above, applicant should delete the added subject matter from the instant application. If the subject matter is not deleted, applicant should delete the benefit claim and/or change the relationship from a CON to a CIP because the instant application contains subject matter not disclosed in the prior-filed applications. Appropriate correction is required because the instant application must be an application for a patent for an invention which is also disclosed in the prior-filed applications, and the disclosure of the invention in the prior-filed application and in the instant application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) except for the best mode requirement. See MPEP 211.05. This objection will not be held in abeyance.
Effective filing dates:
The following claims limitations are not sufficiently described in one or more of the prior-filed applications:
Administration from 5-40 ml of a therapeutic cell suspension (claim 1) is not found in U.S. Provisional Application No. 63/514,580 filed 07/20/2023.
The neurological disease or disorder is trauma to the brain and/or to the spinal cord and/or the spinal ganglions, chronic diseases that affect the central nervous system, diabetes, lupus, post-atherosclerotic stroke or post-hemorrhagic stroke caused by intervertebral disc pathologies (claim 6) is not found in U.S. Provisional Application No. 63/514,580 filed 07/20/2023.
The concentration of cells in the therapeutic cell suspension is from 0.5×105 to 2×107 cells/ml (claim 10) is not found in U.S. Provisional Application No. 63/514,580 filed 07/20/2023.
The method is characterized by a lower rate of side effects associated with intrathecal administration of cells in comparison to a corresponding method comprising intrathecal administering cells at a rate higher than 2 ml/min or in comparison to a corresponding method comprising intrathecal administering a therapeutic cell suspension comprising more than 2×107 cells/ml at a rate higher than 2 ml/min (claim 11) is not found in U.S. Provisional Application No. 63/514,580 filed 07/20/2023.
The side effects include clumping of the administered cells adjacent to the nerve roots (claim 12) is not found in U.S. Provisional Application No. 63/514,580 filed 07/20/2023.
The cells in the therapeutic cell suspension include the progenies and derivatives of induced pluripotent stem cells, genetically manipulated cells transduced to express specific trophic factors or therapeutic factors, or tissue-specific differentiated cells obtained by genetic engineering (claim 13) is not found in U.S. Provisional Application No. 63/514,580 filed 07/20/2023 or U.S. Application No. 18/474,676.
The cells are characterized by simultaneously expressing Oct-4, SSEA4, Nanog, Sox2, KLF4, c-MYC, nestin, β-III tubulin, p75, CD29, CD73, CD90, CD105, and CD166 (claim 14) is not found in U.S. Provisional Application No. 63/514,580 filed 07/20/2023 or U.S. Application No. 18/474,676.
The cells are characterized by simultaneously expressing KLF4, c-MYC nestin, p75, and β-III tubulin and negative for CD45 and CD31 (claim 14) is not found in U.S. Provisional Application No. 63/514,580 filed 07/20/2023 or U.S. Application No. 18/474,676.
Preparing the therapeutic cell suspension includes (i) thawing cryopreserved human stem cells into a solution for injection comprising at least 2 wt% of human serum albumin (HSA), and (ii) washing the cells in the suspension of step (i) with a solution for injection devoid of the HSA to remove the HSA from the suspension, thereby obtaining the therapeutic cell suspension of human stem cells (claim 18) is not found in U.S. Provisional Application No. 63/514,580 filed 07/20/2023 or U.S. Application No. 18/474,676.
Preparing the therapeutic cell suspension includes thawing human stem cells cryopreserved with from 1 to 4 wt% DMSO into a solution for injection thereby obtaining the therapeutic cell suspension, wherein the resulting therapeutic cell suspension comprises less than 0.4 wt% DMSO (claim 19) is not found in U.S. Provisional Application No. 63/514,580 filed 07/20/2023 or U.S. Application No. 18/474,676.
Preparing the therapeutic cell suspension includes (i) thawing human stem cells cryopreserved with from 1 to 4 wt% DMSO into a solution for injection comprising human serum albumin (HSA), and (ii) consequent dilution of the suspension obtained in step (i) with into a solution for injection thereby obtaining the therapeutic cell suspension, wherein the resulting therapeutic cell suspension comprises less than 0.4 v/v% DMSO and less than 0.3 v/v HAS (claim 20) is not found in U.S. Provisional Application No. 63/514,580 filed 07/20/2023 or U.S. Application No. 18/474,676.
Accordingly, claims 1-12 and 16 have an effective filing date of 09/26/2023 based on U.S. Application No. 18/474,676, and claims 13-14, 18-20 have an effective filing date of 07/18/2024 based on internal application PCT/IL2024/050706.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/12/2024 has been considered.
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 by applicant in an information disclosure statement (IDS), they have not been considered.
Claim Objections
The claims are objected to because of the following informalities:
In claim 10, “T The” should be “The” instead.
In claim 15, “CD 73” should be “CD73” instead.
In claim 15, “c-MYC nestin” should be “c-MYC, nestin” instead.
Appropriate correction is required.
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 5, 6 and 12 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.
Claims 5, 6 and 12 each recite an open-ended Markush grouping, i.e., selection from a group “comprising” one or more members. However, a Markush grouping must be a closed group of alternatives, i.e., the selection is made from a group "consisting of" (rather than "comprising" or "including") the alternative members. Abbott Labs., 334 F.3d at 1280, 67 USPQ2d at 1196. The claims are indefinite because it is unclear what other alternatives are intended to be encompassed by the claim. See In re Kiely, 2022 USPQ2d 532 (Fed. Cir. 2022). See, MPEP 2173.05(h). For these reasons, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claims 13-15 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 13 recites the cells are “naïve (undifferentiated) adult stem cells.” The limitation is indefinite because it is unclear if the cells are naïve, undifferentiated or both.
For these reasons, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Dependent claims are included in the basis of the rejection because they do not correct the deficiencies of the claim upon which they depend.
Claims 16-17 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.
The limitation “the spinal needle used for the lumbar puncture” in claim 16 lacks antecedent basis. For these reasons, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Dependent claims are included in the basis of the rejection because they do not correct the deficiencies of the claim upon which they depend.
Claim 17 is 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.
The limitation “the device comprising the therapeutic cell suspension” in claim 17 lacks antecedent basis. For these reasons, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claim 18 is 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.
The limitation “the suspension of step (i)” in claim 18 lacks antecedent basis. For these reasons, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claim 20 is 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 20 recites step “(ii) consequent dilution of the suspension obtained in step (i) with into a solution for injection.” The limitation is indefinite because it is unclear what (1) a “consequent dilution” or (2) the phrase “with into a solution” means. For these reasons, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claim Rejections - 35 USC § 112
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.
Claim 1 recites a method of treating a neurological disease or disorder in a subject in need thereof by administration of a therapeutic cell suspension. Accordingly, the claims are directed to a structurally-undisclosed genus of cell suspension functionally-defined as being therapeutically-effective against any neurological disease or disorder. The cell suspension may broadly comprise any type of cell (e.g., any pluripotent stem cell, any cell of the nervous system, any cell of the pancreas, any cell of the liver, any cell of the immune system, any manipulated cell, any genetically-modified cells, etc.), and the cell suspension may be used to treat any neurological disease or disorder, including, but not limited to, Multiple System Atrophy, Alzheimer's Disease, Pick Disease, Parkinsonism, Idiopathic Parkinson's Disease, Progressive Supranuclear Palsy, Corticobasal Degeneration, Striatonigral Degeneration, Shy-Drager Syndrome, Olivopontocerebellar Atrophy, Huntington Disease, Spinocerebellar Ataxias, Priedreich Ataxia, Ataxia-Telangiectasia, Amyotrophic Lateral Sclerosis, Bulbospinal Atrophy, Spinal Muscular Atrophy, any trauma to the brain and/or to the spinal cord and/or the spinal ganglions, any chronic disease that affects the central nervous system, diabetes, lupus, post-atherosclerotic stroke and post-hemorrhagic stroke caused by intervertebral disc pathologies.
An adequate written description of a cell suspension that treats any neurological disease or disorder requires more than a mere statement that it is part of the invention. What is required is either (1) a description of a common core structure shared among the members (species) of the functionally described genus or (2) a disclosure of a representative number of species of the functionally described genus. It is not sufficient to define a genus of cell suspensions solely by its desired biological property, i.e., the ability to treat any neurological disease or disorder, because disclosure of no more than that, as in the instant case, is simply a wish to know the identity of any cell suspension that is capable of doing so. Also, naming a type of material generically known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material. Thus, claiming all cell suspensions that are therapeutically-effective in treating any neurological disease or disorder, without defining what means will do, or without disclosing a representative number of species, is not in compliance with the written description requirement.
Although the specification contemplates a broad and diverse range of neurological diseases and disorders, ranging from neurodegenerative diseases like Alzheimer’s Disease to genetic neuromuscular disorders like Spinal Muscular Atrophy to chronic autoimmune diseases like diabetes and lupus to brain and spine trauma, the specification does not exemplify the treatment of any neurological disease or disorder by administration of any therapeutic cell suspension. Rather, the working examples exemplify isolation of human oral mucosal stem cells (hOMSCs) and modes of administration thereof.
Accordingly, this limited information is not deemed sufficient to reasonably convey to one skilled in the art that the applicant is in possession of any therapeutic cell suspension capable of treating any neurological disease or disorder at the time the application was filed.
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 1-14, 16-20 are rejected under 35 U.S.C. 103 as being unpatentable over US 2019/117698 A1 to Broeska, Henry Douglas; in view of US 2012/0087869 A1 to Thakker et al.
Broeska discloses a method of treating a vascular-related degenerative neurological disorder in a subject in need thereof comprising a step of intrathecally administering a therapeutic cell suspension. See, Abstract; par. 52-56. A single unit dose contains at least 1×105 stem cells, e.g., 1×106, 4×106, 5×106, 1×107, 5×107, 1×108, and 5×108 stem cells. See, par. 151.
Broeska does not disclose administering a volume ranging 5-40 ml at a rate of 0.1-1.5 ml/min, as instantly claimed in claim 1.
"[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
In this case, the general conditions of the claim are disclosed in Harris, i.e., treatment of a neurological disease or disorder in a subject in need thereof by intrathecally administering a therapeutic cell suspension. The differences between the invention as claimed and that of the prior art are the volume of the cell suspension and the rate of administration. However, one of ordinary skill in the art would have recognized that the volume and administration rate are result-effective variables influencing efficacy of treatment. For example, Thakker discloses a variety of agents have been administered to the cerebrospinal fluid (CSF), typically at flow rates ranging from 0.5-12 ml/min, and broad cerebrospinal fluid (CSF) distribution of an agent can be achievable by delivering the agent in a liquid formulation to the CSF at flow rates less than 500 μl/h. See, Abstract; par. 3-7. Accordingly, one of ordinary skill in the art would have been led to optimize the volume and administration rate through routine experimentation in order to arrive at a more efficacious therapy. For the reasons, absent a secondary consideration, the claimed ranges of 5-40 ml and 0.1-1.5 ml/min would have been prima facie obvious over the prior art. See, MPEP 2144.05.
Regarding dependent claim 2, Broeska teaches a step of performing a lumbar puncture prior to intrathecally administering the therapeutic cell suspension. See, par. 16, 165.
Regarding dependent claim 3, Broeska teaches aspirating 80-150 ml of CSF prior to intrathecal administration of the stem cells. See, par. 165. However, Broeska also teaches that the amount of CSF aspirated is determined by a neurologist based on the size and weight of the patient (par. 165). Accordingly, one of ordinary skill in the art would have recognized that the volume of CSF is a result-effective variable depending on e size and weight of the patient, and, therefore, one of ordinary skill in the art would have been led to optimize the volume through routine optimization. For these reasons, absent a secondary consideration, the limitations of claim 3 also would have been prima facie obvious over the prior art.
Regarding dependent claims 4-6, Broeska teaches the neurological disease is multiple sclerosis or ischemic stroke. See, par. 34-36, 66.
Regarding dependent claim 7, differences in volume and administration rate would have been prima facie obvious for the same reasons provided above.
Regarding dependent claim 8, Broeska discloses a single unit dose contains at least 1×105 stem cells, e.g., 1×107, 5×107 and 1×108 stem cells. See, par. 151.
Regarding dependent claim 9, differences in CSF volume would have been prima facie obvious for the same reasons provided above.
Regarding dependent claim 10, differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. See, MPEP 2144.05. In this case, one of ordinary skill in the art would have recognized that the concentration of a therapeutic composition, or dosage, is a result-effective variable influencing the efficacy of treatment, and, therefore, it would have been prima facie obvious to optimize the concentration through routine experimentation.
Dependent claims 11-12 further recite the method is characterized by a lower rate of side effects associated with intrathecal administration of cells in comparison to a corresponding method comprising intrathecal administering cells at a rate higher than 2 ml/min or in comparison to a corresponding method comprising intrathecal administering a therapeutic cell suspension comprising more than 2x107 cells/ml at a rate higher than 2 ml/min (claim 11), wherein the side effects are selected from the group comprising of back pain, pain in lower limbs, clumping of the administered cells adjacent to the nerve roots, thickening, or mild enhancement of cauda equina nerve roots near the injection site, and any combinations thereof (claim 12).
As instructed by MPEP 2111.04, claim scope is not limited by claim language that does not limit a claim to a particular structure. Further, "the discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003). See, MPEP 2112.
In this case, the limitations of claims 11-12 describe an intended result or functional property of performing the process steps (manipulative actions) positively recited in claim 1. A recitation of an intended result or functional property of the claimed process must result in a manipulative difference between the claimed process and the cited prior art in order to patentably distinguish the claimed process from the cited prior art. If the prior art process is capable of performing the intended result, or if the functional property naturally flows from the prior art process, then the prior art reads on the intended result or functional property recitation. There is no requirement that the cited prior art expressly teach or suggest the intended result or functional property recitation, but only that the subject matter is, in fact, present in the cited prior art. As outlined above, the manipulative actions positively recited by the claims would have been prima facie obvious over the cited prior art. Therefore, the claimed intended results or functional properties of would have naturally flowed from performing the process steps / the structure taught by the prior art. Accordingly, absent evidence to the contrary, the intended result or functional property limitations are not found to patentably distinguish the claimed invention from the cited prior art.
Regarding dependent claims 13-14, Broeska teaches the cells are human stem cells. See, Abstract; par. 101, 158.
Regarding dependent claims 16-17, Broeska teaches withdrawing CSF through a needle via lumbar puncture (spinal tap), and the CSF is reinfused in combination with the stem cells through the same needle during the intrathecal tissue transplant procedure. See, par. 165, 178-180. Rotating and tilting were known means of mixing aqueous formulations prior to the effective filing date of the instantly claimed invention (Official Notice taken, if necessary).
Regarding dependent claims 18-20, Broeska teaches cryopreserving the stem cells in a solution comprising DMSO, and, before infusion, thawing the frozen cell suspension, followed by a wash to remove the DMSO, which is toxic to the stem cells at room temperature. See, par. 172.
Broeska does not teach the cryopreservation solution contains HSA, as instantly claimed.
However, supplementation of cryopreservation solutions with HSA to reduce the freezing point of the solution, minimize intracellular ice formation, and prevent cellular damage was known to in the art prior to the effective filing date of the instantly claimed invention (Official Notice taken, if necessary).
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the invention of Broeska by supplementing the cryopreservation solutions with HSA, as previously known in the art, with a reasonable expectation of success in order to reduce the freezing point of the solution, minimize intracellular ice formation, and prevent cellular damage during cryopreservation.
The claims further recite that the solution initially contains 2 wt% HSA and 1-4 wt% DMSO and, after the wash, 0.4 wt% or 0.4 v/v% DMSO and 0.3 v/v HSA. However, differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. See, MPEP 2144.05. In this case, one of ordinary skill in the art would have recognized that the concentration of DMSO and HSA are result-effective variables influencing the cell viability during cryopreservation and cytotoxicity after thawing, and, therefore, it would have been prima facie obvious to optimize the concentration through routine experimentation.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over US 2019/117698 A1 to Broeska, Henry Douglas; and US 2012/0087869 A1 to Thakker et al., as applied above; in further view of US 2014/0335059 A1 to Pitarua et al.
Regarding dependent claim 15, Broeska does not teach the human stem cells are derived from lamina propria of the oral mucosa, as claimed in dependent claim 15.
Pitarua is relevant prior art for human oral mucosa stem cells (hOMSCs) for treating neurological diseases and disorders, wherein the stem cells are derived from the lamina propria of the oral mucosa. The hOMSCs possess high regenerative capacity regardless of the donor’s age, are readily available, and advantageously provide an autologous stem cell population for treatment of neurological diseases, such as Parkinson’s disease. See, Abstract; par. 17-22, 123-127.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the invention of Broeska by using human stem cells derived from lamina propria of the oral mucosa, as taught by Pitarua, with a reasonable expectation of success because hOMSCs possess high regenerative capacity regardless of the donor’s age, are readily available, and advantageously provide an autologous stem cell population for treatment of neurological diseases, such as Parkinson’s disease.
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.
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Claims 1-17 rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent No. 12,115,196 B1. Although the claims at issue are not identical, they are not patentably distinct from each other because the patent claims anticipate the instant claims
The patent claims a method for treating a neurological disease or disorder in a subject in need thereof comprising (i) a step of performing a lumbar puncture, and (ii) a step of intrathecally administering 5-40 ml of a therapeutic cell suspension at a rate of 0.1-1.5 ml/min, wherein the therapeutic cell suspension comprises a plurality of human stem cells derived from lamina propria of the oral mucosa, wherein the amount of the administered cells is 1×106 to 5×108 (claim 1); the method further comprising drawing 5-40 ml CSF at step (i) and administering a volume of therapeutic cell suspension equal to or up to ±5 ml of the volume of CSF drawn (claim 2); wherein the volume of the therapeutic cell suspension administered essentially equals to the volume of CSF drawn (claim 3); wherein the neurological disease or disorder is a neurodegenerative disease (claim 4); wherein the neurodegenerative disease Multiple System Atrophy, Alzheimer's Disease, Pick Disease, Parkinsonism, Idiopathic Parkinson's Disease, Progressive Supranuclear Palsy, Corticobasal Degeneration, Striatonigral Degeneration, Shy-Drager Syndrome, Olivopontocerebellar Atrophy, Huntington Disease, Spinocerebellar Ataxias, Friedreich Ataxia, Ataxia-Telangiectasia, Amyotrophic Lateral Sclerosis, Bulbospinal Atrophy, Spinal Muscular Atrophy, and combinations thereof (claim 5); wherein the neurological disease or disorder is selected from the group comprising of trauma to the brain and or to the spinal cord and or the spinal ganglions, chronic diseases that affect the central nervous system, diabetes, lupus, post-atherosclerotic stroke and post-hemorrhagic stroke caused by intervertebral disc pathologies (claim 6)’ wherein the method is characterized by (i) a rate of administration of 0.5-1.5 ml/min, (ii) a volume from 5-30 ml of therapeutic cell suspension, and/or (iii) a volume from 5-30 ml of CSF is drawn and a volume of therapeutic cell suspension equal to or up to ±5 ml of the volume of CSF drawn is administered (claim 7); wherein 1×107 to 1×108 cells are administered (claim 8); wherein the concentration of cells in the therapeutic cell suspension is from 0.5×105 to 2×107 cells/ml (claim 9); wherein the method is characterized by a lower rate of side effects associated with intrathecal administration of cells in comparison to a corresponding method comprising intrathecal administering cells at a rate higher than 2 ml/min or in comparison to a corresponding method comprising intrathecal administering a therapeutic cell suspension comprising more than 2x107 cells/ml at a rate higher than 2 ml/min (claim 11); wherein the side effects are selected from the group comprising of back pain, pain in lower limbs, clumping of the administered cells adjacent to the nerve roots, thickening, or mild enhancement of cauda equina nerve roots near the injection site, and any combinations thereof (claim 12); wherein the cells are derived from the lining and masticatory oral mucosa (claim 12); wherein the cells are characterized by simultaneously expressing Oct-4, SSEA4, Nanog, Sox2, CD29, CD73, CD90, CD105, and CD166 (claim 13); wherein the cells are characterized by simultaneously expressing KLF4, c-MYC and nestin, wherein the cells are negative for CD45 and CD31 (claim 14); wherein (i) the therapeutic cell suspension is administered via a spinal needle used for the lumbar puncture, and/or (ii) the therapeutic cell suspension is mixed during the administration to prevent clumping of cells (claim 15); wherein the mixing comprises rotating or tilting the device comprising the therapeutic cell suspension (claim 16). See also, claim 17.
Claims 18-20 rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent No. 12,115,196 B1, as applied above; in view of US 2019/117698 A1 to Broeska, Henry Douglas. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims would have been prima facie obvious over the patent claims and secondary references.
The patent claims do not recite that the cells are cryopreserved prior to administration, as instantly claimed.
Broeska is relevant prior art for teaching a method of treating a vascular-related degenerative neurological disorder in a subject in need thereof comprising a step of intrathecally administering a therapeutic cell suspension. See, Abstract; par. 52-56. Broeska further teaches cryopreserving the stem cells in a solution comprising DMSO, and, before infusion, thawing the frozen cell suspension, followed by a wash to remove the DMSO, which is toxic to the stem cells at room temperature. See, par. 172.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the invention of the patent claims by cryopreserving the cells in a solution comprising DMSO, in view of Broeska, with a reasonable expectation of success because cryopreservation facilitates the viable storage of the therapeutic cells for administration at a later time point.
Broeska does not teach the cryopreservation solution contains HSA, as instantly claimed.
However, supplementation of cryopreservation solutions with HSA to reduce the freezing point of the solution, minimize intracellular ice formation, and prevent cellular damage was known to in the art prior to the effective filing date of the instantly claimed invention (Official Notice taken, if necessary).
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the invention of the patent claims by supplementing the cryopreservation solutions with HSA, as previously known in the art, with a reasonable expectation of success in order to reduce the freezing point of the solution, minimize intracellular ice formation, and prevent cellular damage during cryopreservation.
The claims further recite that the solution initially contains 2 wt% HSA and 1-4 wt% DMSO and, after the wash, 0.4 wt% or 0.4 v/v% DMSO and 0.3 v/v HSA. However, differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. See, MPEP 2144.05. In this case, one of ordinary skill in the art would have recognized that the concentration of DMSO and HSA are result-effective variables influencing the cell viability during cryopreservation and cytotoxicity after thawing, and, therefore, it would have been prima facie obvious to optimize the concentration through routine experimentation.
Conclusion
The following prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Hur et al. (2016) “Intrathecal transplantation of autologous adipose-derived mesenchymal stem cells for treating spinal cord injury: a human trial” The Journal of Spinal Cord Medicine, 39(6), 655-664, discloses the intrathecal transplantation of autologous adipose-derived mesenchymal stem cells for treating spinal cord injury at a dose of 9 × 107 cells in 1 ml suspension over 5 minutes through lumbar spinal tapping. See, Abstract; pg. 657.
Harris et al. (2018) “Phase I trial of intrathecal mesenchymal stem cell-derived neural progenitors in progressive multiple sclerosis” EBioMedicine, 29, 23-30, discloses treating progressive multiple sclerosis (MS) by administering intrathecally (IT) a therapeutic cell suspension comprising autologous bone marrow mesenchymal stem cell-derived neural progenitors (MSC-NPs), wherein administration included up to 107 cells per dose in a 2 ml solution. See, Abstract, Table 1 and page 26.
Lim et al. (2011) “Therapeutic effects of human umbilical cord blood-derived mesenchymal stem cells after intrathecal administration by lumbar puncture in a rat model of cerebral ischemia” Stem cell research & therapy, 2(5), 38, 13 pages, discloses a rat model of cerebral ischemia, wherein, after performing lumbar puncture, 20 μl of a therapeutic cell suspension comprising 106 human umbilical cord blood-derived MSCs (hUCB-MSCs) was intrathecally administered over 30 s. See, Abstract, and Methods: Cell transplantation on pg. 3.
US 2018/0185058 A1 to Anand et al. discloses a method of intrathecal administration comprising determining a total CSF volume of a patient, aspirating a volume of CSF from the patient based on the determined total CSF volume of the patient, and infusing a drug into an intrathecal space of the patient. The “drug” may include stem cells. See, Abstract, and paragraphs 3, 13.
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