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
Election/Restriction
Applicant’s election, without traverse, of Group I, claims 1-5 and 10, drawn to a cell culture of MSCs, in the reply filed on 03/24/2026 is acknowledged.
Applicant nevertheless argues that the cited reference Kriston-Pal does not teach or suggest a combination of essential features of the claimed cell culture of MSCs of claim 1 (Remarks, p. 6-7).
This is not found persuasive because the examiner was able to provide art which satisfied the limitations of product of group I, thereby demonstrating that the asserted special technical feature lacks novelty.
The requirement is still deemed proper and is therefore made FINAL.
Claims 6-9 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claim Status
Claims 1-10 are pending.
Claims 6-9 are withdrawn.
Claims 1-5 and 10 are considered on the merits.
Priority
This application is a 371 of PCT/HU2022/050027 (filed on 03/29/2022), which claims benefit from foreign application Hungary P2100138 (filed on 04/01/2021). The priority claim of the instant application has been granted and the earliest benefit date is 04/01/2021 from the foreign application Hungary P2100138.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 09/28/2023 and 01/22/2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner. The corresponding signed and initialed PTO forms 1449 have been mailed with this action.
Claim Objections
Claims 1-2 are objected to because of the following informalities:
Claim 1 (f), line 1, recites the phrase “in the range 30 to 50”. It is recommended to change to “in the range of 30 to 50” to be consistent with claim 1 (f) and (g).
Furthermore, Claim 1 (f) recites the abbreviation “THBS1”. An abbreviation should be preceded in its first occurrence by the specific identity of the entity which said abbreviation is intended to represent. Thereafter, the use of the abbreviation in the claims will be understood.
Claim 2, end of line 5, recites the term “then”, which should be change to “than”.
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 1-5 and 10 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 recites a list of characteristics of the MSCs. However, there is no conjunction (e.g., “and”, “or”) separating those characteristics. Thus, it is unclear whether the entire list is required or only one from the list. It is noted that under the broadest reasonable interpretation, the claim encompasses that only one option is required (i.e., the listing is separated by the conjunction “or”). For the sake of compact examination, the claim is interpreted as the entire list is required, i.e., the listing is separated by the conjunction “and”. Claims 2-5 and 10 are rejected as being dependent from claim 1 but not resolving the ambiguity.
Claims 1, 3 and 4, at multiple places, recite the term “preferably”, which renders the claims indefinite because it is a subjective term. A claim that requires the exercise of subjective judgment without restriction may render the claim indefinite. See MPEP § 2173.05(b).
Additionally, claims 1 (f) and 2 recite the levels of kynurenine and THBS1 in the unit of “ng/ml” to describe the characteristics of the MSCs. Since it is known that the production levels of kynurenine metabolite and THBS1 cytokine are directly related to the number of the MSCs and the volume of the medium, as evidenced by the instant specification “The measured values were normalized to the cell number after collecting the cells” ([0113]), it is unclear what the reference cell number or the volume of media Applicant intends to use in order to arrive at the claimed levels of kynurenine and THBS1. A claim may be rendered indefinite by reference to term of an object that is variable (see MPEP 2173.05(b), II). The reference cell number and the volume of media required to determine the claimed production levels are 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. For the sake of compact prosecution, claims 1 (f) and 2 are examined as the MSCs produce and release kynurenine and THBS1.
Additionally, claim 2 recites “the separately propagated donations” in line 2. There is insufficient antecedent basis for this limitation because the base claim 1 is silent on “separately” propagated donations.
Claim 3 recites the phrase “the said subject” in line 2. There is insufficient antecedent basis for this limitation because the base claim 1 only recites “donors” but is silent on a subject. This limitation is examined as “the donor”.
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 1-5 and 10 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural product without significantly more. The claim(s) recite(s) a plurality of cultured mesenchymal stem cells (MSCs) that are not markedly different from its naturally occurring counterpart. This judicial exception is not integrated into a practical application because the natural product is not linked to a particular technology. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional limitations are well-understood, routine and conventional in cell biology.
Applicant is directed to the 2019 Revised Patent Subject Matter Eligibility Guidance published in the Federal Register (84 FR 50) on 1/07/2019, which is found at: https://www.govinfo.gov/content/pkg/FR-2019-01-07/pdf/2018-28282.pdf; and the October 2019 Update: Subject Matter Eligibility, which is found at https://www.uspto.gov/sites/default/files/documents/peg_oct_2019_update.pdf.
Briefly summarized here, the new guidance cites a two part test: is the claimed invention directed to a statutory class of invention (Step 1), if so then is the claimed invention as a whole directed to a law of nature, natural phenomena, or an abstract idea (i.e. set forth or described in the claim) (Step 2A, prong one), if so then is the claimed invention recite additional elements that integrate the judicial exception into a practical application (Step 2A, prong two), if not then does the claim as a whole amount to significantly more than the judicial exception (Step 2B).
In regard to Step 1, Claims 1-5 and 10 are drawn to a composition of matter - a plurality of cells.
In regard to Step 2A prong one, Claims 1-5 and 10 are drawn to a nature-based product which is not markedly different from its naturally occurring counterpart. Specifically, independent claim 1 is directed to a plurality of cultured MSCs that have characteristics including (a) being derived from at least two healthy allogeneic donors. (b) being morphologically normal, substantially free of senescent cells; (c) being free of pathogens; (d) being CD105 and CD73 positive but not carrying markers of HSCs or HPCs; (e) the cumulative population doubling being 3 to 14; (f) producing and releasing kynurenine and THBS1, and (g) number of cells being 1 x 105 to 5 x 107. These claims encompass any natural MSCs with the recited characteristics. This option of the claims is a naturally occurring product. Because instant claims are directed to a nature-based product, i.e., a plurality of MSCs, the nature-based product is analyzed to determine whether it has markedly different characteristics from any naturally occurring counterpart(s) in their natural state. Applicant is directed to the publication of Kriston-Pal et al., (Can J Vet Res. 2017;81(1):73-78, of record) evidenced by Kang et al., (J. Vet. Sci. 2012; 13(3): 299-310), Lotfi et al., (Immun Inflamm Dis. 2018;6:448-455) and DuBose et al., (Biochem Biophys Res Commun. 2012;422(3):488-493). Specifically, Kriston-Pal teaches isolating a plurality of MSCs from adipose tissues collected from 13 healthy dogs for therapy (i.e., natural MSCs, e.g., p. 74, left col, para 4), thus teaches a plurality of MSCs that (a) are derived from at least two healthy allogeneic donors. Since the MSCs are for therapy, the MSCs would naturally be (b) morphologically healthy, substantially free of senescent cells and (c) free of pathogens. Kriston-Pal teaches the AT-MSCs are homogenous CD44+ and CD90+ cell population without contaminating cell lineages (e.g., CD34+ and CD45+ cells) (Figure 1A) (p. 77, 1st para.). Kang evidences that the MSCs are positive for CD44, CD73, CD90, and CD105 (e.g., p. 303 and Figs. 2E and 2F). Thus, Kriston-Pal’s MSCs would be (d) CD105 and CD73 positive but not carrying markers of HSCs or HPCs such as CD45 and CD34. Kriston-Pal teaches the AT-MSCs are in Passage 2 (e.g., p. 74, left col, para 4). Kang evidences that Passage 2 AT-MSCs have cumulative population doubling level being more than 4 (e.g., Fig 3), thus evidences Kriston-Pal’s MSCs have (e) the cumulative population doubling being 3 to 14. Lotfi evidences that MSCs produce kynurenine (see e.g., Fig 1A leftmost panel for MSCs producing and releasing kynurenine in the supernatant without stimulation). DuBose evidences that MSCs produce and release thrombospondin 1 (abbreviated as “TSP1”, equivalent to the claimed “THBS1”) (see e.g., Fig 2A for THBS1 in conditioned media released by MSCs maintained in growth media). Thus, Lotfi and DuBose evidence Kriston-Pal’s MSCs (f) produce and release kynurenine and THBS1. Kriston-Pal teaches the MSCs are prepared 12 x 106 cells/injection (p. 74, right col, para “Preparation of AT-MSCs for therapy”), thus teaches the MSCs have (g) number of cells being 1 x 105 to 5 x 107. Thus, instant claims encompass a plurality of cultured MSCs that are identical (no difference in structural or functional characteristics) to naturally occurring MSCs. Furthermore, the fact that instant claims recite “cell culture” or “the MSC culture” does not differentiate the claimed cells from the cells of Kriston-Pal because although the claimed cells may be cultured and propagated for a number of population doublings, they are identical to what exist in nature (i.e., same genotype and phenotype). There is no indication in the specification that culturing MSCs results in the cells having any characteristics (structural, functional, or otherwise) that are different from the naturally occurring cells in their natural state. Because there is no difference between the claimed and naturally occurring cells, the claimed cells do not have markedly different characteristics, and thus are a “product of nature” exception. Accordingly, instant claims are directed to a judicial exception.
In regard to Step 2A prong two, the judicial exception is not integrated into a practical application. In particular, Claims 1-5 and 10 recite no additional elements to integrate the claimed cells into a practical application. Moreover, claims 4 and 5 recite a single additional element of a freezing medium and a pharmaceutically acceptable additive. The terms freezing medium and pharmaceutically acceptable additive are extremely broad and encompass many types of sterile physiological solutions, including culturing buffers. Thus, merely placing the natural product into a generic buffer so that the cell may survive or be cryopreserved does not add a meaningful limitation as it is a nominal extra-solution component of the claim as is a necessary precursor for all of the uses of the cell, and is nothing more than an attempt to generally link the cell product to a particular biotechnology. Clearly, combining the natural cells in a freezing medium or a pharmaceutical additive on its own does nothing to improve a technology, effect a particular treatment, or implement with a particular device to provide a meaningful limitation on the judicial exception. The answer to step 2A prong two is thus “no”.
In regard to Step 2B, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception. As stated supra, Claims 1-5 and 10 recite no additional elements to the MSCs. In regard to claims 4 and 5 reciting a single additional element of freezing medium and pharmaceutically acceptable additive, as discussed above, the additional element of combining a freezing medium and pharmaceutically acceptable additive amounts to no more than a sterile physiological buffer to keep the cells alive or cryopreserved, and do not provide an inventive concept. The answer to question 2B is thus “no”.
Therefore, Claims 1-5 and 10 are directed to a natural cell product, that is not markedly different from its natural counterpart, is not integrate a practical application, and does not include elements that amount to significantly more than the natural product itself and do not qualify as patent eligible subject matter under 35 U.S.C. § 101.
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.
Claims 1-5 and 10 are rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Kriston-Pal et al., (Can J Vet Res. 2017;81(1):73-78, of record), as evidenced by Kang et al., (J. Vet. Sci. 2012; 13(3): 299-310), Lotfi et al., (Immun Inflamm Dis. 2018;6:448-455) and DuBose et al., (Biochem Biophys Res Commun. 2012;422(3):488-493).
With respect to claim 1, it is noted that the preamble “Cell culture of mesenchymal stem cells (MSC)” is interpreted as a plurality of cultured MSCs. Kriston-Pal teaches isolating and culturing a plurality of MSCs from adipose tissues collected from 13 healthy dogs for therapy (e.g., p. 74, left col, para 4), thus teaches a plurality of cultured MSCs that (a) are derived from at least two healthy allogeneic donors.
Since the MSCs are isolated from healthy dogs that “underwent all routine vaccinations and were regularly surveyed by veterinarians” (e.g., p. 74, left col, para 4) and the passage 2 (P2) MSCs are for transplantation (e.g., p. 74, right col, para “Preparation of AT-MSCs for therapy”), the MSCs would naturally be (b) morphologically healthy, substantially free of senescent cells, and (c) free of pathogens.
Kriston-Pal teaches the AT-MSCs are homogenous CD44+ and CD90+ cell population without contaminating cell lineages (e.g., CD34+ and CD45+ cells) (Figure 1A) (p. 77, 1st para.) and teaches the International Society for Cellular Therapy has declared that MSCs must meet 3 criteria, including ii) express CD44, CD90, and CD105, while lacking endothelial and hematopoietic markers CD45, CD34, CD14 or CD11b, CD79a or CD19 (p. 73, left col., last sentence – right col, para 1). Kang evidences that all the MSCs (including AT-MSCs) are positive for CD44, CD73, CD90, and CD105, but negative for hematopoietic and endothelial markers including CD14, CD34, and CD45 (e.g., p. 303 and Figs. 2E and 2F). Thus, Kriston-Pal’s MSCs, as evidenced by Kang, would naturally (d) be CD105 and CD73 positive but not carry markers of HSCs or HPCs such as CD45 and CD34.
Kriston-Pal teaches the AT-MSCs are in Passage 2 (e.g., p. 74, left col, para 4). Kang evidences that Passage 2 AT-MSCs have cumulative population doubling level being more than 4 (e.g., Fig 3), thus evidences Kriston-Pal’s MSCs would naturally have (e) the cumulative population doubling value being 3 to 14.
In regard to limitation (f), as discussed above in the 112(b) rejection, since the reference cell number and the volume of media required to determine the claimed production levels are not defined by the claim or the specification, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention, the limitations regarding kynurenine and THBS1 production levels in clam 1 (f) and claim 2 are examined as the MSCs produce and release kynurenine and THBS1. Lotfi evidences that MSCs produce and release kynurenine (see e.g., Fig 1A leftmost panel for kynurenine in the supernatant released by MSCs without stimulation). DuBose evidences that MSCs produce and release thrombospondin 1 (abbreviated as “TSP1”, equivalent to the claimed “THBS1”) (see e.g., Fig 2A for TSP1 in conditioned media released by MSCs maintained in growth media). Thus, Lotfi and DuBose evidence Kriston-Pal’s MSCs would naturally (f) produce and release kynurenine and THBS1.
Kriston-Pal teaches the MSCs are prepared in a dose of 12 x 106 cells/injection (p. 74, right col, para “Preparation of AT-MSCs for therapy”), thus teaches the MSCs have (g) number of cells being 1 x 105 to 5 x 107.
Furthermore, in regard to the limitations (b) - (f), there is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the time of invention, but only that the subject matter is in fact inherent in the prior art reference. Notably, both the specification and the prior art make clear that the missing descriptive matter is necessarily present in the MSCs described in the reference, and that it would be so recognized by persons of ordinary skill.
Since the Patent Office does not have the facilities for examining and comparing applicants' MSCs with the MSCs of the prior art reference, the burden is upon applicants to show a distinction between the material structural and functional characteristics of the claimed MSCs and the MSCs of the prior art. See In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977) and In re Fitzgerald et al., 205 USPQ 594.
With respect to claim 2, as stated supra, the limitations regarding kynurenine and THBS1 production levels are examined as the MSCs produce and release kynurenine and THBS1. It is noted that the specification defines a balanced MSC composition as that “refers to a preparation of MSCs that are derived from at least two subjects of the same species, the MSCs isolated and selected from the separate donors are mixed in a kynurenine and THBS1 cytokine production-dependent way: fewer cells are dispensed into the end product from those isolated MSCs that produce more kynurenine and THBS1 cytokine and more from those MSCs that produce less kynurenine and THBS1 cytokine, thus, we obtain mixtures of MSCs with similar total kynurenine and total THBS1 cytokine production in the different amplification cycles” (e.g., specification, [0048]). Accordingly, claim 2 is reasonably interpreted as the MSC culture being a mixture of MSCs selected from separately propagated donations, wherein the mixture contains isolated MSCs producing and releasing kynurenine and THBS1 to obtain a certain total production level of kynurenine and THBS1.
As stated supra, Kriston-Pal teaches isolating and culturing MSCs from adipose tissues collected from 13 healthy dogs and teaches the passage 2 MSCs are stored in liquid nitrogen after culturing (e.g., p. 74, left col, para 4). Kriston-Pal continues to teach “Passage 2 AT-MSCs from 2 different adipose tissue donors were thawed, cultured for 3 d, mixed, and suspended” (see p. 74, right col, para “Preparation of AT-MSCs for therapy”), thus teaches a plurality of cultured MSCs that is a mixture of MSCs selected from separately propagated donations (i.e., a mixture of passage 2 AT-MSCs from 2 different donors that are propagated and stored separately). As stated supra, Lotfi and DuBose evidence Kriston-Pal’s MSCs would naturally produce and release kynurenine and THBS1 (see above), thus the mixture of MSCs contains two isolated MSC populations from 2 different donors that each produce and release a certain level of kynurenine and THBS1, so as to obtain a certain total production level of kynurenine and THBS1.
Since the Patent Office does not have the facilities for examining and comparing applicants' MSC mixture with the MSC mixture of the prior art reference, the burden is upon applicants to show a distinction between the material structural and functional characteristics (e.g., the total production levels of kynurenine and THBS1) of the claimed MSC mixture and the MSC mixture of the prior art. See In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977) and In re Fitzgerald et al., 205 USPQ 594.
With respect to claim 3 directed to the donor being a dog, as stated supra, Kriston-Pal teaches isolating and culturing MSCs from adipose tissues collected from 13 healthy dogs (e.g., p. 74, left col, para 4).
With respect to claim 4 directed to the cell culture being a suspension and comprising a freezing medium, as stated supra, Kriston-Pal teaches after culture, the passage 2 MSCs are stored in liquid nitrogen until further usage (e.g., p. 74, left col, para 4), thus teaches the cultured MSCs are in a suspension in a freezing medium.
With respect to claim 5 directed to a balanced MSC composition comprising the MSC culture according to claim 2 and one pharmaceutically acceptable additive, as stated supra, Kriston-Pal, as evidenced by Lotfi and DuBose, teaches a balanced MSC composition comprising the MSC culture according to claim 2. In regard to a pharmaceutically acceptable additive, Kriston-Pal teaches the MSC mixture is suspended in 0.5% sodium hyaluronate and used for in vivo transplantation (see p. 74, right col, para “Preparation of AT-MSCs for therapy”), thus teaches a pharmaceutically acceptable additive.
With respect to claim 10 directed to the balanced composition according to claim 5 being used for the treatment of a subject suffering from osteoarthritis, it is noted that this limitation is interpreted as intended use. MPEP 2111.02 II states “If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention's limitations, then the preamble is not considered a limitation and is of no significance to claim construction”. Thus, the limitation “being used for the treatment of a subject suffering from osteoarthritis” is reasonably interpreted as the balanced composition being capable of performing the intended use to treat osteoarthritis. Nevertheless, Kriston-Pal teaches the MSC mixture is transplanted for the treatment of a subject suffering from osteoarthritis (see p. 74, right col, para “Patient selection”).
Accordingly, Kriston-Pal, as evidenced by Kang, Lotfi and DuBose, anticipates instant claims.
Conclusion
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jianjian Zhu whose telephone number is (571)272-0956. The examiner can normally be reached M - F 8:30AM - 4PM (EST).
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/JIANJIAN ZHU/Examiner, Art Unit 1631
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