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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on Aug. 19, 2025 has been entered.
Claim Status
Claims 1, 4-5, 9-15, and 18 are pending in the application.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-12 and 16-18, in the reply filed on Dec. 18, 2023 is acknowledged. Claims 13-15 are withdrawn for being directed to non-elected subject matter, and claims 1, 4-5, 9-12, and 18 have been considered on the merits.
Claim Interpretation
As “isolated” is not defined by the instant specification (see instant pg. 31, line 30, to pg. 32, line 7), the “isolated” language in the preamble of claim 1 merely implies the claimed NSC population are at least partially free of placenta tissue and/or cell types or other substances without any minimum limitation to the level of isolation or as to what cell types and/or substances may be present so long as 80% by number of the total cells are MHC-IL and CD90H neonatal stromal cells (NSC) and the population as a whole has the recited chondrogenic differentiation and osteogenic differentiation characteristics.
In claim 1, the term “in vitro amplified” is interpreted to require that at least a subset of the NSC cells in the population performed a single cell division in vitro thereby increasing the total number of NSC cells in the population regardless of their MHC-I and CD90 phenotypes or status in the creation of the claimed NSC population. However as the “in vitro amplified” language of the preamble is interpreted as providing no patentable weight to the claimed product because when presented with a given population of NSC, one cannot determine if the cells have been in vitro amplified or not, especially when the number of NSC undergoing cell division can be very few. Notwithstanding this interpretation, all the expressly recited limitations must be met which include the population of NSC has “increased capacity for chondrogenic differentiation as compared to a population of NSC that has not been isolated and in vitro amplified” but does not have “osteogenic differentiation potential as compared to a population of NSC that has not been isolated and in vitro amplified.”
In claim 1, the phrase “do not have osteogenic differentiation potential” means under any conditions wherein any NSC population that has not been isolated and in vitro amplified exhibits differentiation into an osteolineage cell type(s) (e.g., committed osteoprogenitor, preosteoblast, osteoblast, or osteocyte), the claimed NSC exhibit zero differentiation into such osteolineage cell type(s), such as determined by markers including ALPL, RUNX2, and/or calcium deposits (see instant pg. 19, lines 27, to pg. 20, line 7).
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, 4-5, 9-12, and 18 are rejected under 35 U.S.C. 101 because the claimed invention is not directed to patent eligible subject matter. Based upon an analysis with respect to the claim as a whole, claims do not recite something significantly different than a judicial exception. The rationale for this determination is explained below.
The claims are directed to a product described as an isolated population of neonatal stromal cells (NSC) from one or more canine placentas, said population at least 80% by number of neonatal stromal cells of low type I major histocompatibility complex (MHC-IL) phenotype and at least 80% by number of high cluster of differentiation 90 phenotype (CD90H) as determined by recited parameters and wherein the NSC population has been in vitro amplified and the population as a whole has an increased capacity for chondrogenic differentiation and lacks osteogenic differentiation potential as recited in the claims.
The prior art teaches that primary stem cells derived from canine umbilical cord neonatal tissue express MHC-I (MHC Class I) and CD90 when assayed by FACS using indirect immunological labeling with fluorescent-conjugated antibodies (US 20100021436 A1 at Example 2 and Table 1; Salnier et al., Vet Immunol Immunopathol 171: 47-55 (2016) at Table 3, pg. 53, right col., last para.). Thus, it is expected that at least some native NSC from canine placenta would have a high cluster of differentiation 90 phenotype (CD90H) (see instant specification at pg. 13, last para.). Moreover, all nucleated mammalian cells express MHC-I and this expression is known to vary in mesenchymal stromal cells depending on the situation, e.g., with low levels of surface HLA-I observed when in an in vitro culture but higher levels after many passages or in response to inflammatory cues (see e.g., Wang et al., iScience 15: 66-78 (2019) at pg. 73, last para.; pg. 67, para. 4, to pg. 68, para. 2; Fig. 1). Thus, it is expected that at least some native CD90H NSC extracted from canine placenta would also show a MHC-IL phenotype, such as when isolated in vitro or not present in an inflammatory signal microenvironment.
Regarding Step 2A, claims 1 and 4-5 are directed to compositions using only a nature-based product, i.e., a canine neonatal stromal cell(s), even if purified and/or cultured in vitro. In this regard, the claims encompass populations of neonatal stromal cells (NSC) of canine placentas as exist entirely in nature, albeit after an undefined isolation process implied by the preamble of claim 1.
It is only the recited limitations in the claims that are examined under 101 and not aspects such as how the NSC are made or what the cells are intended to be used for. In this case, only an NSC population is examined with respect to its status as judicial exceptions. Thus, the preamble language of “isolated and in vitro amplified” is not limiting to the claimed product unless it implies a structural limitation that is not already positively recited in claim 1. As interpreted in a previous section, claim 1 lacks any recitation of any structural feature(s) that would distinguish the claimed product beyond the implication that the NSC cells are purified away from canine placental tissue such that at least 80% of the neonatal stromal cells have a (MHC-IL) phenotype and a CD90H with complete overlap.
There is not clear evidence in the instant application that MHC-IL and CD90H NSC are not naturally occurring or that the act of purifying (isolating away from tissue) results in any markedly different characteristic from a native placental MHC-IL / CD90H NSC, or a subset population thereof. Furthermore, there is no evidence in the Declaration of Rakic that MHC-IL and CD90H NSC are not naturally occurring or that the act of purifying (isolating away from tissue) and/or de minimus proliferation in vitro results in any markedly different characteristic from a native placental MHC-IL / CD90H NSC, or subpopulation thereof. To the contrary, the evidence cited points to the presence of naturally occurring NSC that are MHC-IL / CD90H, at least in low percentages (Figure A; instant FIG. 12 and 18).
Declaration Fig. A shows before any adhesion step that NSC subpopulations are present in the entire cell population having low MHC-I at 1x10^4 (APC), which can be 5x10^4 or higher (instant FIG. 1C, NSC-1; FIG. 1E, NSC-2) and high CD90 at 10^5 (PE), which can be 1x10^3 or lower (FIG. 1D; FIG. 1E, NSC-1). It is noted that Fig. A of the Declaration of Rakic is only focused on the mean numbers of the NSC population and does not seem to reveal any numerical analyses regarding MFI ratios and high or low thresholds used (see instant Example B), so it is not clear how many cells in the population satisfy the definition of MHC-IL / CD90H of claim 1, which is only population based and not representative of all minority subsets that may be present in natural isolates and which can be preferentially purified and/or amplified in culture.
Similarly the referenced instant FIG. 18 show initial in vitro NSC populations having low MHC-I at 1x10^4 (APC) and high CD90 at 10^5 (PE). FIG. 18 shows NSC subpopulations at P1 with low MHC-I at 10^3 and high CD90 at 10^4. There is not clear evidence that the isolating and/or in vitro amplifying steps changes these naturally occurring subpopulations as oppose to merely increasing the relative percentages of MHC-IL / CD90H NSC subpopulation(s) already present naturally relative to the other cell types. As shown in FIG. 12, the isolated NSC population has heterogenous MHC-I and CD90 expression levels after only two passages, i.e., different subpopulations regarding MHC-I and CD90 phenotypes, which most likely reflects natural subpopulations and not any creation of a new subpopulation post-isolation.
Because there is no difference between the claimed canine placental NSC and naturally occurring NSC, the claimed NSC do not have markedly different characteristics, and thus are a “product of nature” exception. In re Roslin Institute (Edinburgh), 750 F.3d 1333, 1338-39 (Fed. Cir. 2014). Accordingly, the claimed invention is directed to an exception.
Regarding dependent claims 4-5, there is no evidence that the claimed NSC are different from naturally occurring such canine placental NSC subsets regarding doubling capacity and/or immunomodulatory potential. These are considered inherent properties of native cells in placenta from which the claimed product was derived; however, applicant is invited to furnish evidence to the contrary.
Regarding dependent claims 10 and 18, each claims further limits the concentration of the specific NSC cells (e.g., 1 x 106 to 1 x 108 in 0.1 mL to 15 mL or to 5 x 104 to 1 x 109 cells/mL), but again there is no evidence that the concentration of MHC-IL / CD90H NSC alters any characteristic of an MHC-IL / CD90H NSC cell resulting in a markedly different characteristic from a native placental MHC-IL / CD90H NSC. Because there is no difference between the claimed canine placental NSC and naturally occurring NSC beyond concentration/purity, the claimed NSC do not have markedly different characteristics, and thus are a “product of nature” exception. In re Roslin Institute (Edinburgh), 750 F.3d 1333, 1338-39 (Fed. Cir. 2014). Accordingly, these dependent claims are also is directed to an exception.
Thus, an examination of Step 2A prong 1 in the revised 101 guidance, with respect to the claimed invention, the answer is yes because the claimed invention comprises naturally occurring products (judicial exceptions), in the instant case these naturally occurring products are a population of NSC lacking any markedly different characteristic from naturally occurring NSC despite being isolated/purified, or even further concentrated or increased in cell number after isolation.
The limitation to an NSC population having at least 80% by number of NSC of an MHC-IL phenotype and at least 80% by number of a CD90H phenotype, compared to suitable threshold values, is considered as to whether this constitutes any additional element that integrates the judicial exception into a practical application. When examining the claimed invention with regards to Step 2A prong 2, the answer is ‘no’ because the claimed invention does not integrate the judicial exception in the instant case into a practical application. Changing the purity and/or concentration of a natural product from that which exists in a nature does not necessarily integrate the NSC into a practical application (see October 2019 Patent Eligibility Guidance Update at Example 43: Denveric Acid, claim 1; Ass’n for Molecular Pathology v. Myriad Genetics, Inc., 569 U.S. 576 (2013) (isolated BRCA polynucleotides held ineligible)). In the instant case, the cells are both removed away from other cell types (e.g., maternal cells or non-stromal neonatal cells) and increased in concentration without any recited alteration to the structure of said concentrated NSC. Similarly, dependent claims 10, 12, and 18 do not integrate the judicial exception into a practical application by further limiting the concentration and/or purity of the claimed NSC population.
Regarding dependent claims 4-5, there is no indication that the claimed NSC are different from naturally occurring NSC subsets of canine placentas regarding doubling capacity or immunomodulatory potential.
Regarding claims 9-12 and 18, the natural product of NSC derived from nature is combined with a pharmaceutically acceptable vehicle (e.g., saline or an aqueous solution comprising a cryoprotectant) or specifically “in solution with a cryoprotectant.” Again, there is no indication that the claimed NSC cell(s) as limited by claims 9-12 are different from naturally occurring NSC merely because of the presence of the vehicle or cryoprotectant, or by freezing an in vitro NSC population composition. In fact, the instant application teaches that the intent is to maintain the properties of the NSC population (pg. 21, lines 17-26) as NSC cells in the population are intended to function just as naturally occurring NSC, albeit in an isolated and purified form more potent and convenient for administration to a subject. Thus, the combination of the judicial exception in the mixture with the vehicle or cryoprotectant, which may be a non-nature based product, is analyzed (MPEP 2106.04(c)(I)(A)), but there is no indication that mixing these components changes the structure of the NSC nature-based product in a significant or meaningful way to integrate the judicial exception into a practical application.
An examination of Step 2B, the answer is ‘no’ with respect to the claimed invention of claims 1, 4-5, 9-12, and 18. There are no other additional elements recited in the claims that would amount to significantly more than the judicial exception, e.g., the limitation that at least 80% by number of NSC of an MHC-IL phenotype and at least 80% by number of NSC of a CD90H phenotype, the entire NSC population has an increased capacity for chondrogenic differentiation and lacks osteogenic differentiation potential, or as a result of the cell population having been isolated and/or in vitro amplified implying an unrecited structure to the claimed product.
In this case, the fact that the claimed cells may exist in an isolated or more concentrated form does not change the MHC-IL / CD90H NSC in a significant or meaningful way to amount to more than the judicial exception. As noted above, it appears the NSC population of the invention should function like naturally occurring canine MHC-IL / CD90H NSC when using the claimed product, despite changes in cell purity and/or concentration. Moreover, purifying cells from biological samples is well-understood, routine, and conventional for use in increasing the purity and concentration of desired cells in an in vitro container. Similarly, culturing purified cells in vitro is well-understood, routine, and conventional for use in increasing the concentration of desired cells in an in vitro container. Because the claimed invention does not include any additional features that could add significantly more to the exception, the claimed NSC populations do not qualify as eligible subject matter, and should be rejected under 35 U.S.C. § 101.
Regarding claims 9-12 and 18, the natural product of purified NSC derived from nature is combined with a pharmaceutically acceptable vehicle (e.g., sterile water) or specifically in solution with a cryoprotectant. Again, there is no evidence that the claimed NSC as limited by claims 9-12 are different from naturally occurring NSC merely because of the presence of a vehicle or cryoprotectant added by routine and conventional methods for use in storing cells in an in vitro container. Even when considering the combination of the isolated/purified MHC-IL / CD90H NSC being mixed with a pharmaceutically acceptable vehicle and at high cell number concentrations (claims 10 and 18), there is no evidence that this would amount to significantly more than the judicial exception because as noted above neither alone results in any markedly different characteristic from nature and nor does the combination.
Response to Arguments
Applicant’s arguments (pg. 6-9) have been fully considered but not found to be persuasive.
Applicant argues the claims are directed to patent-eligible subject matter due to the preamble language of “an isolated and in vitro amplified” population of NSC implying that the claimed NSC or at least their predecessor cells experienced an adhesion/adherence to a plastic surface (e.g., of a culture plate) termed “plastic adherence” and possibly proliferation. However as indicated in a previous section, claim 1 as a product is interpreted as not being limited by the phrase “in vitro amplified” and is only clearly limited by “isolated” due to the additional express limitation that “the population is at least 80% by number of neonatal stromal cells.” Furthermore, instant lines 14-15 at pg. 32 includes the alternative situation wherein amplification means proliferation on a polymer support, which does not clear limit the polymer to a plastic.
Applicant argues the in vitro amplification limitation of claim 1 implies the claimed NSC cell population possess an increased capacity for chondrogenic differentiation as well as do not exhibit osteogenic differentiation potential; however, it is not clear if this arguments applies to just the MHC-IL / CD90H NSC present or any NSC experiencing the isolation and in vitro amplification as the claimed population may contain as much as 20% NSC that are not MHC-IL / CD90H.
As discussed above, claim 1 is interpreted as a product-by-process such that there are no recited or implied structural feature(s) in the claim that would distinguish the claimed population of MHC-IL and CD90H neonatal stromal cells (NSC) from one or more canine placentas made by a process comprising an in vitro amplifying step from a population of said NSC made by another process lacking any amplifying step. See MPEP 2113. Applicant merely presents argument without clear evidence that there are different biological characteristics and properties implied by “an isolated and in vitro amplified” limitation. And while these purported properties may be established to be a result of isolated NSC manipulations, the patentability of a product-by-process claim relies solely on the claim limitations to the claimed product, either expressly recited or implied, regardless of the process recited in the claim.
In view of the current evidence of record, one cannot assume without evidenced that the MHC-IL and CD90H status is caused solely by isolation and/or in vitro amplification (e.g., on plastic or non-plastic polymer) or even experiencing some other manipulations, such as FACS cell counting/sorting, freezing in commercial cryopreservation medium, and/or optional amplification (instant Example A). Further, one cannot assume without evidence that the MHC-IL and CD90H status is indicative of the presence of the increased capacity for chondrogenic differentiation and lack of osteogenic differentiation relative to non-amplified NSC populations. To establish the above, evidence may be need comparing the properties of a working embodiment to the properties of NSC populations prepared by different processes (e.g., purified without amplification) to ensure the product-by-process recited in claim 1 guarantees the presence of the properties of increased capacity for chondrogenic differentiation and lack of osteogenic differentiation potential as recited.
It is the Office’s position that a claim limited merely by “isolating” naturally occurring stromal cells to an in vitro context and undergoing a nominal cell division step of only a few cells in the population (amplifying) does not per se confer patent-eligibility to any such stromal cell, especially when applicant’s own evidences suggests that freshly isolated NSC populations comprise the claimed cells as minority subpopulations. To the contrary, the markedly different characteristic has to always be present and be shown as markedly different from properties of natural NSC subpopulations. What has been structurally changed about isolated MHC-IL / CD90H NSC claimed to provide increased capacity for chondrogenic differentiation and lack of osteogenic differentiation is not clear and, moreover, it is not clear if these properties are absent from all naturally occurring NSC subsets. As presently worded, the claims are directed solely to a nature-based product despite being the product of a process comprising manipulative steps of isolating and amplifying cells from nature.
Claim Rejections - 35 USC § 112(a), 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, 4-5, 9-12, and 18 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
When the claims are analyzed in light of the specification, the instant invention is directed to a product-by-process comprising isolating canine NSC and in vitro amplifying the NSC to produce an in vitro NSC population comprising at least 80% by cell number NSC having MHC-IL and CD90H phenotypes wherein the NSC population has an increased capacity for chondrogenic differentiation and does not have an osteogenic differentiation potential as compared to a population of NSC that have not been isolated and in vitro amplified.
It must be emphasized that osteogenic differentiation characteristic is a complete lack of any osteogenic differentiation potential. Moreover, osteogenic differentiation could be indicated merely by the increased expression of a single osteogenic marker such as ALPL or RUNX2 under some in vitro cell culture condition.
M.P.E.P. §2163 states “To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventors had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116.”
Firstly, the prior art is silent as to any NSC population completely lacking osteogenic differentiation potential in all circumstances as compared to a positive control of NSC population never experiencing in vitro amplification. Second, there is a lack of evidence in the instant specification as filed that the inventors were in possession of an MHC-IL CD90H canine NSC population completely lacking any osteogenic differentiation potential compared to primary NSC before any in vitro amplification has occurred. Not a single working embodiment is disclosed with empirical evidence of this feature and the silent prior art cannot fill this gap.
The written description requirement may be satisfied through actual reduction to practice 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 structure and function, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of such a specific type of NSC population. In the instant case, the specification fails to provide sufficient descriptive information. Therefore, the skilled artisan cannot envision how to perform the product-by-process and obtain the NSC population claimed, i.e., prophetically lacking any osteogenic differentiation potential, such as wherein 20% of the cells of the population may be MHC-IH CD90L NSC or non-NSC cells (like trophoblasts and hematopoietic stem cells).
35 USC § 112(a), Enablement
Claims 1, 4-5, 9-12, and 18 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification does not enable any person skilled in the art to which it pertains or with which it is most nearly connected to make an MHC-IL CD90H canine NSC population completely lacking any osteogenic differentiation potential, e.g., as compared to primary NSC before any in vitro amplification has occurred.
Enablement is considered in view of the Wands factors (MPEP 2164.01 (a)). The court in Wands states that "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue or unreasonable experimentation. The key word is 'undue.' Not 'experimentation;" (Wands, 8 USPQ2d 104). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighting many factual considerations." (Wands, 8 USPQ2d 1404).
The factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation required is “undue” or unreasonable include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Furthermore, the USPTO does not have laboratory facilities to test if an invention will function as claimed when working examples are not disclosed in the specification. Therefore, enablement issues are raised and discussed based on the state of knowledge pertinent to an art at the time of the invention. And thus, skepticism raised in the enablement rejections are those raised in the art by artisans of expertise. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature and Breadth of the invention:
The claims are directed to a product-by-process comprising isolating canine NSC and in vitro amplifying the NSC to produce an in vitro NSC population comprising at least 80% by cell number NSC having MHC-IL and CD90H phenotypes wherein the NSC population has an increased capacity for chondrogenic differentiation and does not have an osteogenic differentiation potential as compared to a population of NSC that have not been isolated and in vitro amplified. It must be emphasized that osteogenic differentiation characteristic is a complete lack of any osteogenic differentiation potential.
The state of the art:
The prior art does not disclose any canine NSC population that is expressly MHC-IL and CD90H and, thus, does not disclose any properties of such MHC-IL and CD90H canine NSC cells or populations thereof, such as regarding osteogenic differentiation. As the prior art does not disclose working examples expressly creating such cell populations, these aspects must be shown to a reasonable extent so that one of the ordinary skill in the art would be able to practice the invention without any undue burden being on such an artisan, such as to reliably obtain such cell populations, if possible at all.
The amount of direction and guidance and working examples provided by Applicant:
The instant application provides guidance by describing methods of determining osteogenic differentiation potential but fails to show the recited osteogenic differentiation property is present in any MHC-IL and CD90H NSC population using evidence. Thus, there is no evidence provided in the application that the claimed process could be predictably used to make the claimed product as a product-by-process claim format. Instead, the instant specification merely describes prophetic properties regarding osteogenic differentiation without empirical evidence.
The quantity of experimentation needed to make and/or use the invention:
Extensive experimentation would be required to determine how to make MHC-IL and CD90H canine NSC cell populations completely lacking any osteogenic differentiation potential. The science of MSC cell differentiation potential has not evolved such that, without guidance or working examples in the specification (e.g., regarding a nexus between MHC-IL and/or CD90H NSC status and osteogenic differentiation properties and wherein the population is composed 100% by number of such cells), one can predictably obtained the claimed product without undue and unreasonable experimentation, which may never be achieved regarding the claimed osteogenic differentiation feature; however applicant is invited to furnish evidence to the contrary.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 4-5, 9-12, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Kang (US20100021436A1) in view of Yamahara (US20180362922A1), Tarte (Tarte, et al., Blood 115:1549-53 (2009)), Torikai (Torikai et al., Blood 122: 1341-9 (2013)), and Kamishina (Kamishina et al., Am J Vet Res 67:1921-8 (2006), and as evidenced by Wang (Wang et al., iScience 15: 66-78 (2019)).
The claims are interpreted as set forth in previous sections.
Kang teaches isolating and amplifying (culturing) multipotent fetal mesenchymal cells in vitro from canine fetal placenta (e.g., from placental blood) ([0012], [0015], [0001]) wherein the cells show positive antigen expression for both MHC-I (MHC class I) and CD90 ([0015]; [0029]) as determined by FACS ([0039]), and for uses in treating canine diseases ([0073]), such as wherein the cells are grown adhered to plastic ([0015]; [0029]).
Regarding claim 1, Kang does not teach the canine placenta-derived NSC population that comprises at least 80% by number of the cells of the cell population exhibiting both a low type I major histocompatibility complex (MHC-IL) phenotype and a high cluster of differentiation 90 phenotype (CD90H) as determined by flow cytometry wherein the ratio of the mean fluorescence intensity (MFI) between the MHC-I and its control isotype (rMFI) is below a threshold of 20, and when the rMFI between the CD90 marker and its control isotype is above 15, said rMFI being obtained by the double marking of the MHC-I and CD90 markers in flow cytometry as follows: marking of MHC-I, a primary anti-mouse MHC-I IgG2a antibody, revealed with a secondary goat F(ab')2 secondary anti-mouse IgG antibody coupled to allophycocyanin (APC), and marking of CD90, an anti-CD90 monoclonal antibody coupled to phycoerythrin (PE), analysis of a 2D representation of the fluorescence of the APC and PE fluorochromes and comparison with those obtained with the use of the isotypes coupled to the respective fluorochromes.
However Yamahara teaches methods of producing relatively pure in vitro cell populations of greater than 80% CD90+ mesenchymal stem cells (MSCs) derived from neonatal tissue (amnion at birth) by expansion culturing more proliferative MSC cell subsets using subculturing (Example 3, [0253]-[0260]). Flow cytometry using an anti-CD90-FITC labeled antibody was used to show production of mammalian NSC cell populations that were over 80% CD90+ NSC (e.g., main culture 1 at 95%, subculture 1 at 99%, and subculture 2 at 97% CD90+ MSC) ([0260]). Yamahara teaches it is preferable to make cell populations wherein the ratio of CD90+ MSCs in the cell population is preferably 80% or more, further preferably 90% or more, still further preferably 91% or more, still further preferably 92% or more, still further preferably 93% or more, still further preferably 94% or more, still further preferably 95% or more, still further preferably 96% or more, still further preferably 97% or more, still further preferably 98% or more, and still further preferably 99% or more, or having 100% purity ([0148]). Yamahara teaches obtaining stromal stem cells from fetal appendages like the placenta, amnion, and umbilical cord are alternatives to traditional sources like bone marrow and adipose tissue with advantages in being more immunosuppressive for treating immune-related diseases ([0002]-[0003]; [0063]).
Tarte teaches methods of expanding mammalian MSC in vitro to for clinical uses resulting in MSC populations having >90% CD90 expression (a GMP release criterion) as a well-known phenotypic marker of MSC cells and wherein the CD90 mean rMFI is greater than 15 (e.g., 300-400) by fluorescence activated flow cytometry using a PE-labeled monoclonal antibody to CD90, i.e., a high CD90 phenotype (pg. 1550, right col., last para; Table S2, pg. 7, BD clone 5E10).
It would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to make a placental-derived, canine, fetal, NSC population wherein the NSC are CD90+ and MHC-I+ as determined by FACS using a method of Kang modified by Yamahara to increase the purity of CD90+ NSC to at least 80% and wherein the CD90+ is above a FACS determined rMFI threshold above 15, such as a ratio > 35 as taught by Tarte for human MSCs made for clinical use. One of ordinary skill in the art would be motivated to purify the CD90+ multipotent stromal cells for uses in cell therapies for treating canine diseases as taught by Kang to reduce/prevent contamination from non-beneficial or detrimental cell-types (e.g., to reduce possibility of GVHD during allogeneic NSC cell therapies) and especially wherein the method of Yamahara may yield CD90+ NSC cells exhibiting high proliferative capacities. One of ordinary skill in the art would be motivated to specifically use fetal cells from placental tissues for adoptive NSC therapies due to their immunosuppressive characteristics as taught by Yamahara, such as for treating immune-related diseases. Furthermore, it would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to select the canine placental-derived, fetal, CD90+ and MHC-I+ NSC population as above having a high CD90 expression level wherein the FACS-determined rMFI threshold between CD90 and its control isotype is above 15, such as a ratio above 35 or 194 or even higher as taught by Tarte for stromal stem cell preparations made for clinical use wherein the CD90 was marked and analyzed specifically using an anti-CD90 monoclonal antibody coupled to PE in the specific FACS method taught by Tarte.
The combination of Kang, Yamahara, and Tarte does not expressly teach the canine placenta-derived MHC-I+ CD90High NSC population comprises at least 80% cells of the cell population exhibiting an MHC-IL phenotype as determined by an rMFI between the MHC-I and its control isotype below a threshold of 20 using a primary anti-mouse MHC-I IgG2a antibody bound by a secondary goat F(ab')2 secondary anti-mouse IgG antibody coupled to APC, wherein the rMFI is obtained by the double marking of the MHC-I and CD90 markers in flow cytometry, and wherein the analysis of both MHC-I and CD90 expression levels comprises a single two-dimensional (2D) representation of both the APC and PE fluorescence results.
However a low or negative MHC-I expression level is expected and desirable when performing the methods taught by the combination of Kang and Yamahara. All nucleated mammalian cells can express MHC-I and this expression is known to be low in mesenchymal stromal cells of in vitro cultures, at least before many passages (see e.g., Wang et al., iScience 15: 66-78 (2019) at pg. 67, para. 4, to pg. 68, para. 2; Fig. 1 ; pg. 73, last para.). Thus, it is expected that at least some native CD90H NSC extracted from canine placenta would exhibit a MHC-IL phenotype in culture, representing a MHC-IL. CD90H subpopulation. Furthermore, one of ordinary skill in the art with the goal of making canine placental-derived cells for adoptive cell therapies would be motivated to purify the CD90H multipotent stromal cells for treating canine diseases as taught by Kang that are specifically low MHC-I expressors as taught by Torikai below.
Firstly, Kang teaches flow cytometry sorting based on an antibody specifically recognizing an antigen on the cell surface (e.g., MHC class I, CD90, etc.) is fluorescently labeled and the intensity of fluorescence from the labeled antigen-antibody complex is converted to an electric signal, thereby quantifying the amounts of the antigen expressed and wherein cells are stained with antibodies, such as by mixing a fluorescently labeled primary antibody recognizing a surface antigen with a target cell sample or when the primary antibody is indirectly detected by a fluorescently labeled secondary antibody having a binding activity specific for the primary antibody to mark antigen positive cells ([0036]-[0037]; [0039]). Kang teaches it is possible to separate cells expressing a plurality of surface antigens by combining different types of fluorescence used during FACS, including two or more of PE (phycoerythrin), APC (allophycocyanin), FITC (fluorescein isothiocyanate), etc. ([0036]).
Torikai teaches allogeneic adoptive cell therapies can cause immune-mediated rejection due to mismatched MHC-I (e.g., HLA) between donors cells and recipients primarily via host-derived T cells, and that HLA-G can protect donor cells lacking MHC-I expression from recognition by natural killer cells (pg. 1341 to pg. 1342, 1st para., Abstract, pg. 1345, last para., to pg. 1346, 1st para.; pg. 1347, right col., last para.). Because Torikai teaches genetically manipulating cells prior to transplantation to reduce or eliminate MHC-I expression to prevent donor-derived cells from being recognized by resident T cells had not apparent disadvantage but the added advantage that one universal donor cell type can be administered to multiple recipients regardless of MHC-I match (Abstract), one of ordinary skill in the art would be motivated to specifically use NSC cell populations for adoptive NSC therapies having as low of MHC-I expression as possible with no known lower limit, e.g., a low MHC-I phenotype falling well below a rMFI threshold of 20 as determined by FACS.
Kamishina teaches performing FACS analysis of in vitro cultured canine multipotent stromal cells to determine cell surface expression levels of MHC-I using a mouse monoclonal IgG2a antibody labeled by FITC-conjugated rat secondary antibody (Fig. 2; pg. 1922, right col., para. 3-4). Kamishina also teaches determining cell surface expression levels of CD90 using a mouse monoclonal antibody labeled by APC-conjugated secondary antibody and using isotype controls and shows these cells have relatively higher CD90 expression (about 10^3 APC) along with relatively low MHC-I expression (10^1 FITC) (Fig. 2B,D).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to make the canine placental-derived, fetal, CD90High and MHC-I+ NSC population as above wherein the maximum MHC-I expression threshold level is an rMFI between the MHC-I and its control isotype of below 20 as specifically determined using a primary anti-mouse MHC-I IgG2a antibody bound by any appropriate secondary anti-mouse IgG antibody coupled to any first fluorochrome (e.g., a goat F(ab')2 coupled to APC). One of ordinary skill in the art would be motivated to specifically use NSC from placental tissues for adoptive NSC therapies having as low MHC-I expression as possible in view of Torikai in order to avoid complications of immune rejection, need for immunosuppressive drugs, and/or confining transplanted cells to immune privileged sites as noted by Torikai. Furthermore, it would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to select the canine placental-derived, fetal, CD90High and MHC-ILow NSC population as above wherein the rMFI thresholds are obtained simultaneously for convenience by double marking of the MHC-I and CD90 in flow cytometry as above and performing an analysis of a 2D representation of the fluorescence of the APC and PE fluorochromes in comparison with isotype control data. As laid out above, one of ordinary skill in the art would be motivated to quantitate both the MHC-I and CD90 expression levels as suggested by Torikai and Tarte respectively, and as subpopulation percentages as taught by Yamahara, in order to specifically select and further purify NSC that are both CD90High and MHC-ILow, which could conveniently be done simultaneously using FACS as taught by Kang using a single 2D representation of both the first and second fluorochromes to isolate such desired NSC cell subpopulations in vitro for use in therapies.
Kang does not teach the canine placenta-derived NSC population in vitro that comprises at least 80% by CD90H MHC-IL NSC would (1) have an increased capacity for chondrogenic differentiation and (2) lack any osteogenic potential, both as compared to a population of NSC that has never been isolated and in vitro amplified.
Kamishina teaches multipotent stromal cells (mesenchymal stem cells) inherently have the ability to give rise to various cell types of mesodermal origin, including chondrocytes and osteoblasts, when placed in specific conditions in vitro (pg. 1921, 1st para.). Thus, it would have been prima facie obvious to one of ordinary skill in the art motivated to make chondrocytes or analyze the differentiation potential of a population of MSC cells (such as for treating canine musculoskeletal diseases as taught by Kang ([0014])) with a reasonable expectation of success by placing the cells made by a method taught by the combination of Kang, Yamahara, Tarte, Torikai, and Kamishina (e.g., >90% CD90H and MHC-ILow/absent) in an appropriate context to induce chondrogenic differentiation, which would inherently result in increased chondrogenic differentiation compared to a population of NSC that has never been isolated and in vitro amplified.
While the claims lack express recitation of any modified feature of the claimed cells accounting for an increased capacity for chondrogenic differentiation and lack of osteogenic differentiation potential, the claims may be interpreted as implying that collectively all the expressly recited structural features ensure the presence of these functional features, i.e., canine placental-derived, NSC, MHC-IL and CD90H, such as with regard to such NSC that have been experienced both an isolating and an in vitro amplifying at some point.
Although one of ordinary skill in the art would be motivated to differentiate the NSC into chondrocytes to make a cellular therapeutic agents as taught by Kang for treating diseases ([0014]; [0003]; [0007]), whether the differentiation would ever be performed is irrelevant because this increased capacity is an inherent characteristic of the obvious cell population. Also while the art of record does not predict the NSC population would lack an osteogenic differentiation potential as compared to other NSC populations that have never been isolated and in vitro amplified, this is an inherent characteristic of the NSC population (e.g., >90% CD90H and MHC-ILow/absent) taught by the combination of Kang, Yamahara, Tarte, Torikai, and Kamishina.
Regarding claim 4, Tarte teaches methods of producing as many cells as possible at high purity (>90%) for clinical uses by using Good Manufacturing Process protocols in order to prepare CD90High MSC pharmaceutical compositions. Tarte teaches that human BM-MSCs can proliferate in culture for 35-52 population doublings (PD) (pg. 1550, left col., 2nd para.; Figure 1D; pg. 6, 3rd para.). Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to expect canine placental-derived, fetal, CD90High and MHC-I+ NSC population taught by the combination of Kang, Yamahara, Tarte, Torikai, and Kamishina to have a doubling capacity of over 20 cumulative doublings and thus with this motivation from Tarte, it would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to test these cells for doubling capacities over 20 doublings with a reasonable expectation of success and only using routine methods within the skills of the ordinary artisan.
Regarding claim 9, Kang teaches making a cellular therapeutic comprising canine placenta-derived multipotent MHC-I+ CD90+ cells and a cell culture medium (e.g., DMEM, low glucose+20% FBS; see instant specification at pg. 21, lines 20-22), such as for treating a canine musculoskeletal disease (Abstract; [0019]; [0047]).
Regarding claims 10 and 18, Kang does not expressly teach wherein the pharmaceutical composition comprises 1x106 to 1x108 cells in 0.1-15 mL.
However Yamahara teaches pharmaceutical compositions comprising the pharmaceutically acceptable vehicle of a culture medium ([0011]) and a population of in vitro cultured, multipotent, CD90High stromal cells (CD90+ neonatal mesenchymal stem cells) ([0011]; [0144]; [0194]) wherein the composition specifically comprises 2.0×107 cells/mL or less of placental derived NSC (amniotic) ([0207]) or 2.3×108 placental derived NSC in 25 mL of medium (Example 6, [0272]). Note, a prima facie case of obviousness can exists when a claimed range overlap ranges disclosed in the prior art. See MPEP 2144.05. Thus, it would have been prima facie obvious to one of ordinary skill in the art motivated to make a pharmaceutical composition with the cells made by a method taught by the combination of Kang, Yamahara, Tarte, Torikai, and Kamishina (e.g., >90% CD90H and MHC-ILow/absent), including within a range of 1x106 to 1x108 cells in 0.1-15 mL as taught by Yamahara or comprising between 5 x 104 to 1x109 cells/mL as also taught by Yamahara.
Regarding claims 11-12, Kang does not teach a frozen 0.1-15 mL pharmaceutical composition comprising from 1 x 106 to 1 x 108 NSC cells and a cryoprotectant. However Yamahara specifically teaches wherein the pharmaceutical composition comprises 2.0×107 cells/mL or less of placental derived MSC (amniotic) and cryopreservatives for cell stimulation by freezing-thawing ([0207]). Thus, Yamahara teaches a frozen 0.1-15 mL composition comprising a cryoprotectant and 1 x 106 to 1 x 108 NSC cells (e.g., 2.0×107) as a suitable intermediate for use in methods for producing relatively pure in vitro cell populations of greater than 80% CD90+ mesenchymal stem cells (MSCs) derived from neonatal tissue by expansion culturing more proliferative MSC cell subsets using subculturing.
Thus, the claimed invention as a whole is prima facie obvious to one of ordinary skill in the art before the effective time of filing in the absence of evidence to the contrary.
Response to Arguments
Applicant’s arguments (pg. 9-15) regarding the previous obviousness rejections are found persuasive; however, Applicant's claim amendments necessitated the new ground(s) of rejection presented above.
As laid out above, the prior art teaches how to isolate and culture canine placenta-derived, neonatal multipotent stromal cell (NSC) populations, said populations comprising NSC subpopulations having both a CD90H phenotype and a MHC-IL phenotype, and the prior art provides motivations to intentionally select, proliferate, and enrich such cell populations wherein CD90 expression is considered CD90H as defined in claim 1 and MHC-I expression is as low as possible when preparing NSC for uses in allogeneic adoptive cell therapies, including to purity levels of at least 80% or higher.
Applicant traverses the previous rejection in part by arguing the cited prior art fails to provide a motivation to intentionally select/purify/enrich those NSC cell populations that are MHC-IL / CD90H; however these motivations are provided in the rejection above with Kang teaching the CD90H phenotype is expected inherently by performing the method and low or negative MHC-I expression level is desirable when making canine placental-derived cells for allogenic adoptive cell therapies in view of Torikai teaching mismatched MHC-I (e.g., HLA) between donors cells and recipients can cause immune-mediated rejection and that cell populations having low MHC-I represent a more “universal” type donor cell save for administration to subjects having any MHC alleles. Furthermore, merely purifying a low MHC population is much easier and safer than genetically modifying cells destined for adoptive cell therapies to lack MHC-I expression.
Thus, the prior art motivates intentionally purifying MHC-IL NSC populations for use in adoptive cell therapeutic applications. While the prior art does not expressly motivate to intentionally purify such cells wherein they are also CD90H, in view of the prior art teachings, the NSC populations taught by Kang are already CD90H and methods of Kang are merely being modified or instructed by teachings in Yamahara, Tarte, Torikai, and Kamishina. Furthermore CD90 is a core identifying marker of NSC generally and the minimum required CD90 expression to meet the definition of CD90H in claim 1 is relatively low, e.g., the rMFI between the CD90 marker and its control isotype is above 15 (instant Example B).
Although the prior art does not appreciate all the characteristics of the claimed NSC cell population render obvious to make as laid out above, the characteristics of increased chondrogenic differentiation and lack of osteogenic differentiation are considered inherent. As the combination of Kang, Yamahara, Tarte, Torikai, and Kamishina teaches the method steps required to make the claimed product, the recited characteristics (capabilities and potentials in an intended use) are expected to be present absent evidence to the contrary. As noted in MPEP 2112(II), it is not required that an inherent feature or property be recognized by the prior art, and thus the conclusion that the recited properties are inherent to isolated and purified MHC-IL / CD90H canine NSC cells and/or the aforementioned after experiencing culturing in vitro for sufficient time to expand.
Applicant’s response also argues that the claimed product has advantageous characteristics of: proliferative capacity (Example C.1; FIG. 4), chondrogenic differentiation potential (Example C.2; FIG. 5), limited osteogenesis (Example C.3) useful for treating osteoarthritis, and, upon intra-articular arthrotherapy, the ability to colonizing hyaline articular cartilage to promote tissue repair/regeneration. However these characteristics are considered inherent to the in vitro NSC population rendered obvious to make by methods taught by the combination of Kang, Yamahara, Tarte, Torikai, and Kamishina. The claimed cell population product is directed to high-purity MHC-IL / CD90H NSC taught by the combination of Kang, Yamahara, Tarte, Torikai, and Kamishina as evidenced by Wang, with sufficient motivations to make such populations regardless of whether any of these advantageous characteristics were appreciated prior to the filing date. In particular, evidence presented above shows a sound basis for believing that the NSC populations taught be the prior art would reasonably be expected to have a consecutive cell doubling capacity greater than 20 cumulative doublings as expressly recited in claim 4.
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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1, 4-5, 9, and 11 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2 and 8-13 of copending Application No. 17/790,269 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because claims 10-12 in the reference application is directed to a composition comprising cells consisting solely of neonatal placental stromal cells (NSCs) having both MHC-IL and CD90H phenotypes and wherein the NSCs are in a composition (e.g., a solution) comprising a pharmaceutically acceptable vehicle (e.g., a solution comprising a cryoprotectant). The reference claims differ from instant claims 1 and 9 in that the cells are generic to any neonatal mammal (instead of specifically canine) and the exact threshold value cutoffs for the MHC-IL and CD90H phenotypes are not limited as defined in instant claim 1.
However, the reference claims clearly encompass canine cells (see reference specification at [0069], [0097], [0165]) and wherein the purity of the NSC population is at least 80% by number, e.g., at least 85% or 90%, such as by intentionally sorting the cells by flow cytometry with this aim ([0101], [0074]; [0110]). The reference application (US20230008313A1) also specifically defines at [0107] that NSC are termed “MHC-IL/CD90H” if the ratio of the median fluorescence intensity (MFI) between the MHC-I and its control isotype (also referred to as relative MFI or rMFI) is below a threshold of 20, more particularly 15, more particularly 10, and if the rMFI between the CD90 marker and its control isotype is above 50, more particularly 20. On the other hand, a population or sub-population of NSC is termed MHC-IH/CD90L if the ratio of the median fluorescence intensity (MFI) between the MHC-I and its control isotype is above 20, more particularly 15, more particularly 10, and if the rMFI between the CD90 marker and its control isotype is below 15, more particularly 20. Furthermore the reference claims encompass wherein the MHC-IL and CD90H phenotypes are based on flow cytometry of simultaneously co-marked NSC samples (double marking) using a primary anti-mouse MHC-I IgG2a antibody (e.g., DG-BOV2001/DG-H58A) and a secondary goat F(ab′)2 secondary anti-mouse IgG antibody coupled to APC along with an anti-CD90 monoclonal antibody coupled to PE (e.g., YKIX337.217(PE)) as analyzed using a 2D representation of both the APC and PE fluorescent outputs and compare to isotype coupled to the same respective fluorochromes ([0102]-[0106]).
The reference claims do not expressly disclose the population of NSCs of phenotype MHC-IL/CD90H (1) having an increased capacity for chondrogenic differentiation and (2) lacking any osteogenic potential compared as compared to a population of NSC that has never been isolated and in vitro amplified. However both of these characteristics are presumed to be inherent to canine placental-derived MHC-IL / CD90H NSC cultured in vitro until clear evidence is provided to the contrary, such as wherein the percentage of these cells is high (e.g., greater than 80, 90, 99%). Furthermore regarding instant claims 4-5, the canine MHC-IL/CD90H NSC disclosed by reference claims 2 and 8-13 inherently possess the characteristics of doubling capacity (claim 4) and immunomodulatory potential (claim 5) recited in the claims.
Regarding instant claim 9, the reference claims teach freezing said NSCs in a pharmaceutical composition comprising a pharmaceutically acceptable vehicle in the form of a solution comprising a cryoprotectant (cryoprotector).
Regarding instant claim 11, the reference claims teach wherein the NSC population is frozen in a composition comprising a cryoprotectant (cryoprotector).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 4-5, 9, and 11 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2 and 8-13 of copending Application No. 17/790,269 (reference application) as applied above, and further in view of Tarte and Long (Long et al., Cytometry A 93: 82-92 (2018)).
Regarding instant claim 4, the MHC-IL/CD90H NSC rendered obvious above by reference claims 2 and 8-13 inherently possess the characteristics of doubling capacity (claim 4) and immunomodulatory potential (claim 5) recited in the claims. Furthermore as evidenced by Tarte, human MSC are capable of proliferating in culture for 35-52 population doublings (PD) (pg. 1550, left col., 2nd para.; Figure 1D; pg. 6, 3rd para.). Thus, it would have been prima facie obvious to one of ordinary skill in the art to find MHC-IL/CD90H NSC populations disclosed by reference claims 2 and 8-13 to have a doubling capacity of over 20 cumulative doublings, such as by using methods and assays taught by Tarte. Regarding instant claim 5, as evidenced by Long, canine placental derived fetal MSC (cPMSC) exhibit immunomodulatory functions in the form of secreting IL-6 and IL-8 (Fig. 3; pg. 89, right col., last para.). Thus, it would have been prima facie obvious to one of ordinary skill in the art to expect MHC-IL/CD90H NSC populations disclosed by reference claims 2 and 8-13 to have an immunomodulatory potential and to show this by using methods and assays known in the prior art, e.g., as taught by Long.
Claims 1, 9-11, and 18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2 and 8-13 of copending Application No. 17/790,269 (reference application) as applied above, and further in view of Yamahara.
Regarding instant claim 10, the reference claims teach wherein the NSC population is in a composition comprising a cryoprotector (e.g., in a frozen state); however, the reference claims do not suggest wherein the frozen pharmaceutical composition is a volume of 0.1-15 mL comprising from 1 x 106 to 1 x 108 NSC cells. But Yamahara specifically teaches a pharmaceutical composition comprises 2.0×107 cells/mL or less of placental derived MSC (amniotic) and cryopreservatives ([0207]). Thus, Yamahara teaches a frozen 0.1-15 mL composition comprising a cryoprotectant and 1 x 106 to 1 x 108 NSC cells (e.g., 2.0×107). Thus, it would have been prima facie obvious to one of ordinary skill in the art motivated to make a pharmaceutical composition with the MHC-IL/CD90H NSC rendered obvious by reference claims 2 and 8-13 in a frozen 0.1-15 mL composition comprising a cryoprotectant and 1 x 106 to 1 x 108 NSC cells as taught by Yamahara.
Regarding instant claim 18, the reference claims do not suggest wherein the pharmaceutical composition comprises 5x104 to 1x109 cells/mL. However Yamahara teaches pharmaceutical compositions comprising the pharmaceutically acceptable vehicle of a culture medium ([0011]) and a population of in vitro cultured, multipotent, CD90High stromal cells (CD90+ neonatal mesenchymal stem cells) ([0011]; [0144]; [0194]) wherein the composition specifically comprises 2.0×107 cells/mL or less of placental derived NSC (amniotic) ([0207]) or 2.3×108 placental derived NSC in 25 mL of medium (Example 6, [0272]). Thus, it would have been prima facie obvious to one of ordinary skill in the art motivated to make a pharmaceutical composition with the MHC-IL/CD90H NSC rendered obvious by the reference claims wherein the number of cells is between 5 x 104 to 1x109 cells/mL as taught by Yamahara.
Response to Arguments
Applicant’s double patenting response (pg. 15) is considered to be non-responsive. 37 C.F.R. 1.111(b) requires applicants to respond to each rejection with “arguments pointing out the specific distinctions believed to render the claims, including any newly presented claims, patentable over any applied references.” For each rejection, for example, applicants might provide a proper terminal disclaimer (or at least indicate a willingness to submit one when double patenting is the only remaining issue); explain why the rejection is overcome by amendments; provide convincing arguments that the rejection was made in error; and/or explain why amendments or claim cancellations in the copending applications have rendered the rejection moot. If any of the conflicting pending application matures to a patent, modifying the rejection to account for claim-number changes will not constitute a new ground of rejection.
Conclusion
No claim is allowed.
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/ERIC J ROGERS/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638