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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 June 24, 2025 has been entered.
Claim Status
Claims 1-19 and 21-23 are currently pending in this application. Claims 13-19 and 21 are withdrawn for being directed to non-elected subject matter, and claims 1-12 and 22-23 have been considered on the merits.
Previous Rejections
Status of the rejections: the previous claim rejections under 112(d) and 102 are withdrawn.
Claim Interpretation
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 MSCs in the claimed cell culture product from other cell culture compositions comprising mesenchymal stem cells (MSCs) made by a different process and placed in a basal medium comprising an EpCAM polypeptide. See MPEP 2113. When presented with a population of MSCs, one cannot determine if the MSCs have been expanded in the presence of an isolated EpCAM polypeptide or not, regardless of the EpCAM amount. Thus, the cell culture product of claims 1-12 is interpreted as comprising any mesenchymal stem cells (MSCs) because the process used in making the cells is given no patentable weight when no structure is implicitly required beyond what is expressly recited in the claims.
In the claims, the term “basal medium” is interpreted as any aqueous solution or hydrogel compatible with vertebrate cell culture that comprises essential ingredients for mesenchymal stem cell growth including a carbon source, nitrogen source, mineral salts (e.g., phosphate source), and vitamins as well as other optional ingredients such as glutamine, various amino acids, lipids, etc. (see instant [0057]). Under a broadest reasonable interpretation, the term “medium composition comprising “a basal medium” encompasses blood, plasma, and other extracellular fluids of a vertebrate body.
In the claims, the term “isolated EpCAM polypeptide” is interpreted to encompass any naturally occurring epithelial cell adhesion molecule (EpCAM) protein, and any portion thereof (e.g., a peptide, Eρ-ICD, or full-length EpCAM) or any peptide sequence having at least 85% sequence identity thereto or any functional variant thereof, e.g., that enhances cell proliferation or multipotency of an MSC (see instant [0002]; [0004]; [0043]-[0044]). The term “isolated” is interpreted as being non-limiting as the EpCAM polypeptide must merely be a component of the claimed composition and, thus, cannot be “isolated” regardless of its provenance or the claim being in the form of a product by process.
In the claims the step “cultured” and the phrase “in an amount effective in promoting expansion and/or multipotency of the MSCs” is interpreted as either a method of making and/or an intended use for the claimed cell culture product. Thus, the amount of EpCAM polypeptide and any function in promoting expansion or multipotency of an MSC is irrelevant to the product as presently claimed. In claims 1-8 and 10-11, the intended use or process of making the product comprising “an amount effective in promoting expansion and/or multipotency” of the MSCs of interest does not provide any limitation because what constitutes such an amount has no definition or lower limit in the claims or the instant specification and is instead a purely results-defined variable absent evidence to the contrary, such as varying with the amount of cells present, type of MSC, temperature, presence of non-MSC cells, and/or the medium composition.
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 1-12 and 22-23 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 interpreted as explained in a previous section.
Claims 1-12 and 22-23 are directed to a product described as a “cell culture product” comprising mesenchymal stem cells (MSCs), a basal medium, and an EpCAM polypeptide, which can be made by a process of culturing MSC with an amount of isolated EpCAM polypeptide effective to promote MSC expansion and/or multipotency or which may be used in a process of culturing MSCs thereby promoting expansion and/or multipotency.
The prior art teaches that MSC isolated from nature are conventionally kept viable in cell culture conditions, such as media (Harichandan, Best Pract Res Clin Haematol 24: 25-36 (2011) at pg. 25 to pg. 26, 2nd para.). Thus, a cell culture composition comprising MSCs and a medium necessarily involves a product of nature. Furthermore as set forth in a previous section, the term “basal medium” encompasses any aqueous composition comprising a carbon source, nitrogen source, mineral salts, and vitamins suitable for MSC viability, which encompasses various natural compositions, including blood and other extracellular fluids.
In the claims, the term “isolated EpCAM polypeptide” encompasses naturally occurring “polypeptides,” including relatively large peptides (e.g., ~ 30 amino acid residues) as well as full-length EpCAM proteins, which are naturally occurring transmembrane proteins. For example, the prior art teaches the EpCAM fragments EpEX and EpICD are naturally occurring EpCAM polypeptides (Schnell et al., Biochim Biophys Acta 1828: 1989-2001 (2013) at Fig. 4-6).
Therefore, the claimed invention encompasses a mixture consisting entirely of three naturally occurring components, or alternatively, at least one product of nature (MSCs) combined with, at most, two synthetic ingredients: a synthetic basal medium and a synthetic EpCAM polypeptide.
It is only the recited limitations in the claims that are examined under 101 and not aspects such as how the claimed cell culture product or MSCs are made or what the product is intended to be used for. In this case, only an in vitro MSC population in a basal medium composition comprising an EpCAM polypeptide is examined with respect to its status as judicial exceptions.
Regarding Step 2A, claims 1-11 encompass compositions using only nature-based products (e.g., MSCs, a body fluid, and an EpEX EpCAM polypeptide) even if the MSCs or EpCAM polypeptide is highly-purified/enriched compared to a natural state and/or in an in vitro medium. In this regard, the claims encompass populations of MSC as exist in nature, albeit after placement in a composition comprising other products of nature or at most 1 or 2 non-natural ingredients (the basal medium and/or a synthetic EpCAM polypeptide).
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 MSCs may be isolated and placed in an in vitro composition related to cell culturing, which encompasses natural body fluids like MSC interstitial fluids and synovial fluids. There is no evidence in the instant application that the MSCs, the EpCAM polypeptide, or the medium composition necessarily have any feature that is markedly different from naturally occurring MSCs, EpCAM polypeptides, or extracellular body fluids. Thus, the claimed cell culture product is directed a “product of nature” exception. In re Roslin Institute (Edinburgh), 750 F.3d 1333, 1338-39 (Fed. Cir. 2014).
Regarding claims 2-11, there is no evidence that the claimed cell culture products of these dependent claims have any implied structure based on the process used to make them that is markedly different from naturally occurring MSCs that have been isolated. Furthermore, the medium encompasses naturally occurring fluids, and the EpCAM polypeptide encompasses natural occurring EpCAM molecules. Thus, the claimed cell culture product encompass compositions that are merely a mixture of 1-3 natural products. Accordingly, the claimed invention is directed to an exception.
Claim 12 differs in that the medium (e.g., the basal medium) is limited to a synthetic medium comprising specifically recited components. While the concentration of the EpCAM polypeptide being 1-50 µg/mL in the composition may encompass artificial situations; at a static point in time (e.g., upon ingredient mixing), the MSCs are not markedly different by merely being placed in the presence of such artificial concentrations of EpCAM polypeptide and a synthetic basal medium.
Claims 22-23 differ from claims 1-12 in that the medium is limited to a synthetic basal medium and the EpCAM polypeptide must comprise an extracellular domain, which encompass the naturally occurring fragment EpEX known in the prior art (Schnell at Fig. 5). The nature of the MSCs and natural EpCAM fragment are not markedly different from their natural counterparts as a result of combining these two products of nature and merely placing them in a synthetic cell culture medium, e.g., comprising Dulbecco's modified Eagle's medium (DMEM) supplemented with 5 % to 25% FBS. While the concentration of the EpCAM polypeptide being 1-50 µg/mL in the composition may encompass artificial situations; at a static point in time (e.g., upon ingredient mixing), the MSCs are not markedly different by merely being placed in the presence of such artificial concentrations of EpCAM polypeptide and either a naturally occurring or synthetic basal medium.
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 1-3 naturally occurring products (judicial exceptions). In the instant case, these naturally occurring products are a population of MSC lacking any markedly different characteristic from naturally occurring MSC and optionally a naturally occurring EpCAM polypeptide and/or extracellular body fluid, which despite being mixed together in a composition with the potential for emergent properties, none has been identified.
In addition, claims 1-2, 4, 7-8, and 10 encompass some human blood samples as evidence by the prior art, see e.g., Li, S., et al., Stem Cells Transl Med 4: 359-68 (2015) and Gervasoni, A., et al., Oncol Rep 25: 1669-703 (2011). Li teaches human peripheral blood comprises MSCs (Abstract), and Gervasoni teaches the extracellular domain of EpCAM is present in the peripheral blood of colorectal cancer patients, e.g., detected by a CellSearch assay based on immunological recognition of extracellular EpCAM (Table 3; pg. 1672, left col., 2nd para.). Furthermore, human blood comprises a carbon source (e.g., glucose), nitrogen sources (amino acids such as glutamine), mineral salts (e.g., iron, zinc, selenium, and calcium), vitamins (e.g., C, folate, B6, A and D), antibiotics (e.g., defensins and immunoglobulins), and by definition serum and serum ingredients, and furthermore blood may function as a basal medium for MSCs (Frank et al., J Clin Lab Anal 26: 317-20 (2012) at Abstract; Labow and Souba, World J Surg 24: 1503-13 (2000) at 1503, left col., 1st para.; Kalantar and Kopple, Adv Ren Replace Ther 10: 170-82 (2003) at Abstract; Openheim et al., Ann Rheum Dis 62 Suppl 2: ii17-21 (2003) at Table 1). Thus, claims 1-2, 4, 7-8, and 10 read on blood samples from human colorectal cancer subjects. Regarding claim 11, human blood naturally comprises the glucocorticoids cortisol and aldosterone, amongst others (Andersen, K., Curr Hypertens Rep 15: 484-8 (2013) at pg. 484, right col., 2nd para.), and the phosphate source ATP (Bohmer et al., Chem Biol Interact 160: 159-64 (2006) at pg. 162, right col., last para.).
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 MSC cells or EpCAM polypeptide into a practical application (see October 2019 Patent Eligibility Guidance Update at Example 44: 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 and possibly increased in concentration without any recited alteration to the structure of said cultured/expanded MSC. There is no indication that the MSC of the claimed product are necessarily different from naturally occurring MSC, such as regarding any structural feature related to an MSC function, e.g., differentiation potential. Similarly, if the EpCAM polypeptide is a naturally occurring EpEX and/or the basal medium is merely a naturally occurring extracellular body fluid, there is no indication that the EpCAM or basal medium of the claimed product are necessarily different from their naturally occurring counterparts beyond a change in concentration and/or purity. Furthermore, absent evidence to the contrary, the mere combining of these three ingredients together does not necessarily result in markedly different characteristics for any of these products of nature as compared to their individual natural counterparts.
An examination of Step 2B, the answer is ‘no’ with respect to the claimed invention of claims 1-12 and 22-23. There are no other additional elements recited in the claims that would amount to significantly more than the judicial exception. The fact that the claimed product may comprise MSCs and/or EpCAM polypeptide in an in vitro isolated or more concentrated form does not change the MSCs or EpCAM polypeptide in a significant or meaningful way to amount to more than the judicial exception. Moreover, purifying MSCs and polypeptides away 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 MSCs in an in vitro container. Because the claimed invention does not include any additional features that could add significantly more to the exceptions, the so called cell culture products claimed do not qualify as eligible subject matter, and should be rejected under 35 U.S.C. § 101.
Response to Arguments
The arguments of 6/24/25 regarding the previous 101 rejections were fully considered but not found to be persuasive.
Applicant traverses the previous rejection by arguing that claim 1 recites a cell culture product made artificially and comprising the EpCAM polypeptide in an amount effective in promoting expansion and/or multipotency of the MSCs and argues as this feature defines the structure or constitution of the claimed cell culture product, it represents a structural limitation other than intended use as well as something markedly different from nature.
As set forth fully above, the claimed invention is directed to a composition comprising three components: (1) MSCs, (2) EpCAM polypeptide, and (3) basal medium. The first two components encompass naturally occurring species while the third component is typically artificial in nature but without a clear definition in the specification reads on natural fluids of living vertebrates.
Applicant's arguments are not found persuasive when the MSCs are not indicated to have any markedly different unnatural characteristic, the EpCAM polypeptide is not limited to ones producing an nonnatural effect or result on said MSCs, and the basal medium merely preserves the MSCs as they would grow in nature. Absent evidence to the contrary, the purified EpCAM polypeptide and/or basal medium is not indicated as providing the composition as a whole or the MSC therein with any markedly different characteristic from nature. When viewed as a static product as claimed, how the MSCs, medium, and EpCAM polypeptide came to be together in a single composition is neither relevant or discernable, such as whether the EpCAM or media component(s) were ever isolated or human-made, especially when the EpCAM polypeptide and medium composition as claimed are interpreted to read on products of nature as well. Absent evidence to the contrary, the natural species of EpCAM polypeptide and medium compositions have the same functions as they do in nature, i.e., are structurally identical.
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 1-12 and 22-23 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.
The claims are interpreted as explained in a previous section.
When claims 1 and 8-12 are analyzed in light of the specification, the instant invention is broadly directed to a composition comprising (1) MSCs, (2) a basal medium, and (3) any EpCAM polypeptide, which may be isolated, capable of promoting the expansion or multipotency of a type of MSC.
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 inventor 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.”
It must be emphasized that the scope of the claimed EpCAM encompasses a broad genus of structures, including relatively long peptides and any naturally occurring full-length EpCAM, which are type I transmembrane proteins of about 35 kDa in size, and any fragment thereof (e.g., its EpEx or EρICD) as well as sequence variants thereof, such as non-naturally occurring variants of such fragments that potentially function to promote expansion or multipotency of a type of MSC (see instant [0002]; [0004]; [0043]-[0044]). Thus, the instant invention is broadly directed to a composition comprising any EpCAM polypeptide, which optionally had been previously isolated, that might function to promote expansion or multipotency of at least one type of MSC, at least at certain amounts in a cell culture product under certain conditions.
There is insufficient written description in the specification to reasonably convey to one skilled in the relevant art at the time the application was filed that the inventors had possession of the claimed genus of EpCAM polypeptides, particularly smaller EpCAM polypeptide species (e.g., EpICD having only about 26-30 amino acid residues), isolated full-length EpCAM polypeptides, or any EpCAM polypeptide comprising a transmembrane domain.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described such that one of skill in the art can envision all the structures therein. While the structures of various species of the genus are adequately described, their function in promoting expansion or multipotency of an MSC is not.
The instant specification describes various EpCAM polypeptide structures as noted above but only a single species of any of these structures being capable of increasing human BM-MSC cell expansion or multipotency. Only a single human EpEX EpCAM polypeptide (SEQ ID NO: 2) is shown in any of the working examples ([0092]-[0100]; FIG. 1, Table 1; [0110]). Furthermore, this EpCAM polypeptide was shown under certain conditions to limit multipotency instead of promote it by pushing MSCs specifically to osteolineages and away from, e.g., adipocyte lineages and chondrolineages ([0105]; [0111]; FIG. 6).
There is a lack of evidence in the instant specification as filed that the inventors were in possession of any EpCAM polypeptide capable of increasing the expansion or multipotency of any MSC beyond the naturally occurring EpCAM fragment (SEQ ID NO: 2) of human EpCAM. This is not a representative number of species for the entire claimed genus of EpCAM polypeptides as defined by the instant specification ([0002]; [0004]; [0043]-[0044]). Furthermore in the working examples, the effect of the EpCAM fragment polypeptide consisting of instant SEQ ID NO: 2 was only shown on human cells and more specifically toward human bone-marrow MSCs.
Moreover, any EpCAM polypeptide comprising a transmembrane domain is not likely to be effective after isolation when placed in a medium composition due to insolubility and/or precipitation affecting polypeptide folding and ligand accessibility. Further, the skilled artisan might deduce that something in the extracellular domain of EpCAM is both necessary and sufficient for the requisite function, meaning the limitations of instant claims 2-3 and 5-6 appear to be required.
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 a genus of antibodies as claimed. In the instant case, the specification fails to provide sufficient descriptive information. The general knowledge and level of skill in the art do not supplement the omitted description because specific, not general, guidance is what is needed.
Therefore, the skilled artisan cannot envision all the EpCAM polypeptides encompass by claims 1-6 and 8-12. For example, the specification does not provide any disclosure or guidance as to a nexus between essential EpCAM extracellular domain structure(s) and the function of increasing expansion and/or multipotency of any MSC.
Regarding claims 7 and 22-23, while the EpCAM polypeptide genus of each of these claims is described sufficiently to show possession in some situations, this is only for when the MSCs are the type of MSCs that respond to the species of each particular EpCAM polypeptide genus, e.g., mammalian MSCs under certain conditions, e.g., near a physiological temperature, presence/absence of differentiation factors, etc., as shown in the working examples or further supported in light of the prior art.
35 USC § 112(a), Scope of Enablement
Claims 1-12 and 22-23 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because while the claims are enabled for wherein the EpCAM polypeptide comprises the extracellular domain of human EpCAM SEQ ID NO: 2 and is soluble in basal media; 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/use any EpCAM polypeptide merely functionally defined as promoting expansion and/or multipotency of MSCs in cell culture media under any conditions.
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 of the invention:
The claims are directed to compositions comprising an EpCAM polypeptide in amounts effective in promoting expansion and/or multipotency of at least one population of MSCs during culturing.
Breadth of the claims
The claims are broadly directed to wherein the MSCs are any type of MSCs and the EpCAM polypeptide is only functionally defined as ones that are effective in promoting expansion and/or multipotency the MSC in at least in one cell culture condition and one medium composition.
In the instant case, there is insufficient description in the specification that the inventors had enabled the claimed genus of EpCAM polypeptides as structurally described by the instant specification ([0002]; [0004]; [0043]-[0044]).
The state of the art:
The prior art is silent as to increasing the expansion or multipotency of an MSC population by contacting it with an EpCAM polypeptide.
The amount of direction and guidance and working examples provided by Applicant:
The instant application provides generic guidance by listing possible EpCAM polypeptides, such as any functional fragment and synthetic sequence variants without guidance as to which EpCAM structures are suitable for providing the EpCAM function and requisite amount of claim 1.
Only a single human EpCAM polypeptide (EpEX SEQ ID NO: 2) is shown in any of the working examples and only at a single concentration of 3 µg/mL ([0092]-[0100]; FIG. 1, Table 1; [0110]). Furthermore, this EpCAM polypeptide was shown under certain conditions to limit multipotency instead of promote it by pushing MSCs specifically to osteolineages and away from, e.g., adipocyte lineages and chondrolineages ([0105]; [0111]; FIG. 6).
Furthermore, it is not clear from the instant application what amount is effective in promoting expansion but not multipotency or vice versa effective in promoting multipotency but not expansion as implied the doctrine of claim differentiation in view of dependent claim 8.
Moreover, any EpCAM polypeptide comprising a transmembrane domain is not likely to be effective after isolation when placed in a medium composition due to insolubility and/or precipitation affecting polypeptide folding and ligand accessibility as well as altering its effective concentration, if any.
Regarding claims 7 and 22-23, while the EpCAM polypeptide genus of each of these claims is described sufficiently to show enablement in some limited situations (e.g., human EpCAM and human MSC and EpCAM polypeptide at a concentration of about 3 µg/mL), this is only for when the MSCs are the type of MSCs that respond to the species/sequence of each particular EpCAM polypeptide of the genus, e.g., mammalian MSCs under certain conditions, e.g., near a physiological temperature, presence/absence of differentiation factors, etc., as shown in the working examples or further supported in light of the prior art.
The quantity of experimentation needed to make and/or use the invention:
Extensive experimentation would be required to determine the EpCAM polypeptides paired with responding types of specific MSCs encompassed by the claims from these two broad genera. The science of biomedical research has not evolved such that, without guidance or working examples in the specification regarding a nexus between a structural feature of the species of EpCAM polypeptides (e.g., from fish, reptiles or rodents) encompassed by the claims and various MSC cell types (e.g., from fish, reptiles or rodents); to make/use the full scope of the claimed invention without undue and unreasonable experimentation, which may never be achieved across the entire scope. Similarly, without guidance or working examples in the specification regarding a nexus between a structural feature of the species of EpCAM polypeptide comprising at least 90% sequence identity to instant SEQ ID NO: 2 and consisting only of EpCAM extracellular domain(s) encompassed by the claims with the MSC cell type which responds beyond human BM-MSC; one cannot make/use the full scope of the claimed invention without undue and unreasonable experimentation, which may never be achieved across the entire scope of EpCAM polypeptides and MSCs.
In summary, claims 1-12 and 22-23 are rejected under 35 U.S.C. 112(a) because the specification does not reasonably provide enablement, to a person skilled in the art to which it pertains or with which it is most nearly connected to, to make and use the claimed invention. The limited guidance provided in the specification, the lack of guidance in the prior art, and the broad scope of the claims with regard to possible EpCAM structures and choice of MSC; undue and unreasonable experimentation would have been required for one skilled in the art to produce the recited result, which may never be achieved across the entire scope of the claims.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-3, 5-6, and 8 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Endaya (Endaya et al., Oncotarget 8: 54629-39 (2017)).
The claims are interpreted as explained in a previous section. Moreover, for purposes of applying prior art to a product claim, intended use language is not given patentable weight unless the intended language imparts an implied limitation to the product.
Regarding claims 1 and 8, Endaya teaches medium compositions comprising multipotent MSCs and EpCAM: MSCs in Huh7-conditioned media (CM), Huh7 cell cultures, or HCC 26-1004 cell cultures (pg. 54631; Fig. 1A; Suppl. Fig. 1C). Endaya teaches the Huh7-CM and Huh7 cell cultures comprise full-length EpCAM, EpICD, and secreted EpEx, which affects MSC behavior (Fig. 2B-D; Suppl. Fig. 2).
Regarding claim 2, Endaya discloses wherein the EpCAM polypeptide comprise an extracellular domain of EpCAM (full-length EpCAM and/or EpEx) (pg. 54631; Fig. 1A; Suppl. Fig. 1C).
Regarding claims 3 and 5, Endaya discloses wherein the EpCAM polypeptide is a fragment that does not comprise an intracellular domain of EpCAM or a transmembrane domain (EpEx or EpICD) (id.).
Regarding claim 6, Endaya discloses wherein the EpCAM polypeptide is the extracellular domain of EpCAM (EpEx) (id.).
Thus, Endaya anticipates the claimed invention.
Claims 1-8 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Endaya (Endaya et al., Oncotarget 8: 54629-39 (2017)) and further as evidenced by P16422 (UniProt P16422 (13-NOV-2007)).
Regarding claim 4, Endaya does not expressly teach any sequence information for the human EpCAM polypeptide(s) present in their compositions but as instant SEQ ID NO: 1 is a human EpCAM sequence, Endaya inherently teaches claim 4, wherein the EpCAM polypeptide is at least 90% identical to SEQ ID NO: 1, as evidenced by P16422 disclosing an identical sequence for the full-length human EpCAM as shown below.
ID EPCAM_HUMAN Reviewed; 314 AA.
AC P16422; P18180; Q6FG26; Q6FG49; Q96C47; Q9UCD0;
DT 01-AUG-1990, integrated into UniProtKB/Swiss-Prot.
DT 13-NOV-2007, sequence version 2.
DE RecName: Full=Epithelial cell adhesion molecule;
DE Short=Ep-CAM;
DE AltName: Full=Adenocarcinoma-associated antigen;
DE AltName: Full=Cell surface glycoprotein Trop-1;
DE AltName: Full=Epithelial cell surface antigen;
DE AltName: Full=Epithelial glycoprotein;
DE Short=EGP;
DE AltName: Full=Epithelial glycoprotein 314;
DE Short=EGP314;
DE Short=hEGP314;
DE AltName: Full=KS 1/4 antigen;
DE AltName: Full=KSA;
DE AltName: Full=Major gastrointestinal tumor-associated protein GA733-2;
DE AltName: Full=Tumor-associated calcium signal transducer 1;
DE AltName: CD_antigen=CD326;
DE Flags: Precursor;
GN Name=EPCAM; Synonyms=GA733-2, M1S2, M4S1, MIC18, TACSTD1, TROP1;
OS Homo sapiens (Human).
Query Match 100.0%; Score 1619; Length 314;
Best Local Similarity 100.0%;
Matches 314; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MAPPQVLAFGLLLAAATATFAAAQEECVCENYKLAVNCFVNNNRQCQCTSVGAQNTVICS 60
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Db 1 MAPPQVLAFGLLLAAATATFAAAQEECVCENYKLAVNCFVNNNRQCQCTSVGAQNTVICS 60
Qy 61 KLAAKCLVMKAEMNGSKLGRRAKPEGALQNNDGLYDPDCDESGLFKAKQCNGTSMCWCVN 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 KLAAKCLVMKAEMNGSKLGRRAKPEGALQNNDGLYDPDCDESGLFKAKQCNGTSMCWCVN 120
Qy 121 TAGVRRTDKDTEITCSERVRTYWIIIELKHKAREKPYDSKSLRTALQKEITTRYQLDPKF 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 TAGVRRTDKDTEITCSERVRTYWIIIELKHKAREKPYDSKSLRTALQKEITTRYQLDPKF 180
Qy 181 ITSILYENNVITIDLVQNSSQKTQNDVDIADVAYYFEKDVKGESLFHSKKMDLTVNGEQL 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 ITSILYENNVITIDLVQNSSQKTQNDVDIADVAYYFEKDVKGESLFHSKKMDLTVNGEQL 240
Qy 241 DLDPGQTLIYYVDEKAPEFSMQGLKAGVIAVIVVVVIAVVAGIVVLVISRKKRMAKYEKA 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 DLDPGQTLIYYVDEKAPEFSMQGLKAGVIAVIVVVVIAVVAGIVVLVISRKKRMAKYEKA 300
Qy 301 EIKEMGEMHRELNA 314
||||||||||||||
Db 301 EIKEMGEMHRELNA 314
Regarding claim 5, Endaya does not expressly teach any sequence information for the human EpEX present in their compositions, but as instant SEQ ID NO: is 2 a human EpCAM extracellular domain sequence, Endaya inherently teaches claim 5, wherein the EpCAM polypeptide is at least 90% identical to SEQ ID NO: 2, as evidenced by P16422 disclosing an identical sequence is present in the prototypical full-length human EpCAM as shown below.
100.0% identity in 265 residues overlap; Score: 1392.0; Gap frequency: 0.0%
Sequence1 1 MAPPQVLAFGLLLAAATATFAAAQEECVCENYKLAVNCFVNNNRQCQCTSVGAQNTVICS
Sequence2 1 MAPPQVLAFGLLLAAATATFAAAQEECVCENYKLAVNCFVNNNRQCQCTSVGAQNTVICS
************************************************************
Sequence1 61 KLAAKCLVMKAEMNGSKLGRRAKPEGALQNNDGLYDPDCDESGLFKAKQCNGTSMCWCVN
Sequence2 61 KLAAKCLVMKAEMNGSKLGRRAKPEGALQNNDGLYDPDCDESGLFKAKQCNGTSMCWCVN
************************************************************
Sequence1 121 TAGVRRTDKDTEITCSERVRTYWIIIELKHKAREKPYDSKSLRTALQKEITTRYQLDPKF
Sequence2 121 TAGVRRTDKDTEITCSERVRTYWIIIELKHKAREKPYDSKSLRTALQKEITTRYQLDPKF
************************************************************
Sequence1 181 ITSILYENNVITIDLVQNSSQKTQNDVDIADVAYYFEKDVKGESLFHSKKMDLTVNGEQL
Sequence2 181 ITSILYENNVITIDLVQNSSQKTQNDVDIADVAYYFEKDVKGESLFHSKKMDLTVNGEQL
************************************************************
Sequence1 241 DLDPGQTLIYYVDEKAPEFSMQGLK
Sequence2 241 DLDPGQTLIYYVDEKAPEFSMQGLK
*************************
Thus, Endaya as evidenced by P16422 anticipates the claimed invention.
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 1-3, 5-6, 8, and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Endaya (Endaya et al., Oncotarget 8: 54629-39 (2017)).
The claims are interpreted as explained in a previous section.
As set forth fully above, Endaya anticipates claims 1-8 and, thus, renders obvious the subject matter of claims 1-3, 5-6, and 8.
Regarding claim 10, Endaya teaches standard media may be used (pg. 54637, left col., 1st para), including media for the Huh7 cells such as a DMEM medium containing 10% FBS (pg. 54637, right col., 1st para.) and additionally, standard DMEM comprises glutamine. Endaya also teaches using Lonza MSCGM® medium for maintaining the MSCs (pg. 54637, left col.) and this commercial basal medium contains a serum ingredient (FBS), glutamine, and the antibiotics penicillin, streptomycin, gentamicin, and amphotericin. Thus, Endaya teaches the subject matter of claim 10 and the claimed invention as a whole is prima facie obvious to one of ordinary skill in the art before the earliest effective time of filing in the absence of evidence to the contrary.
Claims 1-3, 5-6, 8, and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Endaya (Endaya et al., Oncotarget 8: 54629-39 (2017)) in view of Khoo (Khoo et al., Stem Cells Dev 17: 883-96 (2008)).
The claims are interpreted as explained in a previous section.
As set forth fully above, Endaya anticipates claims 1-8 and, thus, renders obvious the subject matter of claims 1-3, 5-6, and 8.
Regarding claim 11, Endaya does not expressly teach using a standard medium comprising all three of a serum ingredient, a corticosteroid and a phosphate source.
However Khoo teaches maintaining MSCs in a basal medium (DMEM-LG) comprising a serum ingredient (BSA), the corticosteroid dexamethasone, and the phosphate source ascorbic acid 2-phosphate (pg. 884, left col., last para.).
It would have been prima facie obvious to one of ordinary skill in the art before the time of filing when performing a method taught by Endaya to make a composition comprising multipotent MSCs mixed with Huh7-CM comprising EpEx or a Huh7 cell composition comprising full-length EpCAM EpICD, and secreted EpEx wherein the composition comprises a standard basal medium comprising a serum ingredient (BSA), a corticosteroid (dexamethasone), and phosphate (ascorbic acid 2-phosphate) as taught by Khoo. One of ordinary skill in the art would be motivated by the wording of Endaya to use any standard cell culture medium, such as DMEM-based media, and Khoo teaches a medium (DMEM-LG) with these specific ingredients is favored for maintaining multipotent MSCs (pg. 884, left col., last para., to right col., 1st para.).
Thus, the claimed invention as a whole is prima facie obvious to one of ordinary skill in the art before the earliest effective time of filing in the absence of evidence to the contrary.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERIC J ROGERS whose telephone number is (571)272-8338. The examiner can normally be reached Monday - Friday 9:00-6:00.
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/ERIC J ROGERS/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638