DETAILED ACTION
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 .
Status of the Claims
Claims 1-22 responsive to communications on 01/14/2025 are pending.
Claims 1-22 have been examined on their merits.
Claim Objections
Claim 13 is objected to for the following informalities: the claims recites “13..” and therefore, has a redundant period. Eliminating the extra period would be ameliorative.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
In multiple instances the specification recites references to websites with hyperlinks (see paragraph [0099, 0121, 0125, 0158]). Removing the top-level domain name without any prefix such as http:// would be ameliorative.
The specification also recites multiple references to color in the drawings (e.g., green, blue, yellow, and orange, paragraph [0037]; “color references” (paragraph [0038]; green and red (paragraph [0039]). However, a petition to use color drawings has not been submitted and approved. Applicant should eliminate reference to color in the drawings.
Drawings
The drawings are objected to under 37 CFR 1.83(a) because they fail to show details as describes in the specification as described in the specification. Specifically, the drawings (Figs. 1-15) are illegible. Any structural detail that is essential for a proper understanding of the disclosed invention should be shown in the drawing. MPEP § 608.02(d). Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 3-6, 12-13, 15-16, and 20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 3-5 and 15-16, Where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999). The terms “2-dimensional esophageal cells” and “3-dimensional esophageal cells” are used in the claims to refer to cells that have been cultured in 2-dimensional or 3-dimensional format (conditions) (“a 2-dimensional format (i.e. on a tissue culture dish or a glass cover-slip), or in a 3-dimensional format (i.e. organoids, spheroids)”, see paragraph [0127]). The plain (and therefore, accepted) meaning of “2-dimensional esophageal cells” and “3-dimensional esophageal cells” is that the cells themselves are 2-dimensional or 3-dimensional. However, objects that take up space, are in fact “3-dimensional”. Therefore, since esophageal cells take up space they are “3-dimensional esophageal cells” and cannot be “2-dimensional esophageal cells.” For compact prosecution, the claims have interpreted to refer to the conditions of culturing, not the literal dimensions of the cells. Claims 15 and 16 are indefinite for similar reasons. Specifically, the claims refer to “2-dimensional” or “3-dimensional” stratified esophageal epithelia, but instead appear to refer to 2-dimensional and 3-dimensional culturing conditions.
Regarding claims 6, 12-13, and 16, these claims exemplary language (“e.g., a human subject”, “e.g., 2-dimensional”, “e.g., 3-dimensional”, “e.g., 3 dimensional esophageal organoid tissue”, in claims 6. 12-13, and 16, respectively). Exemplary language renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). For compact prosecution, this exemplary language has been considered optional.
Claim 20 contains the trademark/trade name “Matrigel.” Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe soluble basement membrane matrix cells, and, accordingly, the identification/description is indefinite.
Claim Rejections - 35 USC § 112(a)
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 19 and 20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 19 requires “wherein the culturing further comprises seeding the esophageal cells onto solubilized basement membrane matrix cells”.
Claim 20 requires “wherein the solubilized basement membrane matrix cells are matrigel cells”.
The plain language of the claim requires seeding esophageal cells onto other cells which are “solubilized basement membrane matrix cells” and “matrigel cells” specifically.
Under the written description guidelines (see MPEP 2163) the Examiner is directed to determine whether one skilled in the art would recognize that the Applicant was in possession of the claimed invention as a whole at the time of filing. The following considerations are critical to this determination.
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. An original claim may lack written description support when (1) the claim defines the invention in functional language specifying a desired result but the disclosure fails to sufficiently identify how the function is performed or the result is achieved or (2) a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). The written description requirement is not necessarily met when the claim language appears in ipsis verbis in the specification. “Even if a claim is supported by the specification, the language of the specification, to the extent possible, must describe the claimed invention so that one skilled in the art can recognize what is claimed. The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement.” Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 968, 63 USPQ2d 1609, 1616 (Fed. Cir. 2002).
Accordingly, to satisfy the written description requirement, the 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. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.
Actual Reduction to Practice
In regards to claims 19 and 20, while the specification asserts “In some embodiments, the culturing further comprises seeding the obtained esophageal cells onto solubilized basement membrane matrix cells . . . In some embodiments, the solubilized basement membrane matrix cells are matrigel cells” (paragraph [0020]), the specification does not provide examples of seeding esophageal cells onto other cells which are “solubilized basement membrane matrix cells” and “matrigel cells” specifically.
Rather, the specification only demonstrates that cell can be cultured in or on Matrigel (which is trademarked brand name for a solubilized basement membrane matrix (paragraphs [0091, 0121]) (a type of extracellular matrix frequently used in cell culture).
State of the Art and Quantity of Experimentation
The method of making the claimed invention is not well established, because the art is completely silent as to culturing cells on solubilized basement membrane matrix cells, including matrigel cells.
Specifically, solubilized basement membrane matrix and Matrigel specifically are extracellular matrices, not cells (see as evidenced by Xian (US20160237400A1, on IDS 06/15/2026), methods for expanding esophageal cells (claims 1 and 10) can be performed on Matrigel, a basement membrane matrix (paragraphs [0037, 0210]).
Thus, performing a method of culturing cells on solubilized basement membrane matrix cells, including matrigel cells was not well established.
Conclusion
Applicant has claimed culturing cells on solubilized basement membrane matrix cells, including matrigel cells, yet the specification has not disclosed culturing cells on solubilized basement membrane matrix cells, including matrigel cells. Rather, the specification demonstrates culturing cells on solubilized basement membrane matrix, including Matrigel.
Furthermore, the state of the art indicated that culturing cells on solubilized basement membrane matrix cells, including matrigel cells is not well established.
Therefore, the Examiner concludes that there is insufficient written description of the instantly claimed limitation of culturing cells on solubilized basement membrane matrix cells, including matrigel cells.
Indeed, the specification instead demonstrates culturing cells on solubilized basement membrane matrix, including Matrigel.
Therefore, the Examiner concludes that a person of ordinary skill in the art would find that the specification inadequately describes the claimed method of culturing cells on solubilized basement membrane matrix cells, including matrigel cells.
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 21 and 22 are rejected under 35 U.S.C. 101 because the claimed invention is directed to natural phenomenon (natural product) without significantly more.
Applicant is directed to the subject matter eligibility test for products processes (MPEP 2106; specifically, MPEP 2106(III) flowchart).
Briefly summarized here, the new guidance cites a two part test: is the claimed invention directed to a statutory class of invention (Step 1), if so then is the claimed invention as a whole directed to a law of nature, natural phenomena, or an abstract idea (i.e. set forth or described in the claim) (Step 2A, prong one), if so then is the claimed invention recite additional elements that integrate the judicial exception into a practical application (Step 2A, prong two), if not then does the claim as a whole amount to significantly more than the judicial exception (Step 2B).
In regards to Step 1, the claimed inventions (claims 21 and 22) are directed to compositions which are a statutory class of invention (Step 1: YES).
In regards to Step 2A, prong one, independent claim 21 is drawn to a composition comprising or consisting of expanded esophageal cells produced in vitro from the method of Clam 1.
Similarly, independent claims 22, is a kit comprising or consisting of expanded esophageal cells produced in vitro from the method of Clam 1.
Thus, both claims 21 and 22 require the expanded esophageal cells produced in in vitro in Claim 1.
Independent claim 1 itself, is a method comprising culturing obtained esophageal cells in vitro, wherein the culturing of the obtained esophageal cells results in expanded esophageal cells, wherein the culturing comprises seeding the obtained esophageal cells with a growth medium comprising hydrocortisone, epidermal growth factor (EGF), a rho-kinase inhibiting agent, a Wnt signaling pathway activating agent, a TGFβ inhibiting agent, and a BMP inhibiting agent.
According to the specification, the “obtained” esophageal cells are “comprised within a biopsy sample from a subject (e.g., a human subject)” or “comprised within a surgical specimen sample from a subject (e.g., a human subject)” (paragraph [0026]), and therefore, derive from natural tissues (i.e., are primary cells as understood in the art; see paragraph [0044] “Clinical Characteristics of Primary Human Esophageal Samples for 2D or 3D in vitro culture” referring to Fig, 15).
As further demonstrated in the specification, according to Example I, “To characterize the esophagus, we obtained normal/healthy squamous epithelial (normal squamous—“NS”) adult human biopsies” (paragraph [0075]). According to Example II, “To demonstrate the ability of HYENAC media to support long-term esophagus cultures, matched cells from biopsies used to generate scRNA-seq data in FIG. 2 were plated on the day biopsies were obtained” (paragraph [0080]).
Thus, the obtained esophageal cells explicitly derive from natural tissues.
As further evidenced by Xian (US20160237400, on IDS 06/15/2026), it was known in the art before the effective filing date that natural cells including esophageal cells could be obtained from from in vivo samples (paragraphs [0028-0030]).
While claim 1 performs method step (expanding the obtained esophageal cells in a growth medium comprising hydrocortisone, epidermal growth factor (EGF), a rho-kinase inhibiting agent, a Wnt signaling pathway activating agent, a TGFβ inhibiting agent, and a BMP inhibiting agent), this merely expands these cells and does not result in cells with markedly different characteristic to their natural counterparts.
Regarding assessing markedly different characteristics in compositions claims, Applicant is directed to MPEP 2106.04(c)(I)(A), where the claim is to a nature-based product by itself (e.g., a claim to “a Lactobacillus bacterium”), the markedly different characteristics analysis should be applied to the entire product. See, e.g., Chakrabarty, 447 U.S. at 305, 309-10, 206 USPQ at 195, 197-98 (applying analysis to entire claimed “bacterium from the genus Pseudomonas containing therein at least two stable energy-generating plasmids, each of said plasmids providing a separate hydrocarbon degradative pathway”).
Additionally, Where the claim is to a nature-based product in combination with non-nature based elements (e.g., a claim to “a yogurt starter kit comprising Lactobacillus in a container with instructions for culturing Lactobacillus with milk to produce yogurt”), the markedly different characteristics analysis should be applied only to the nature-based product limitation. For instance, for the yogurt starter kit example, the Lactobacillus would be analyzed for markedly different characteristics. The container and instructions would not be subject to the markedly different characteristics analysis as they are not nature-based products, but would be evaluated as additional elements in Prong Two (and Step 2B if needed) if it is determined that the Lactobacillus does not have markedly different characteristics from any naturally occurring counterpart and thus is a product of nature exception. See, e.g., Funk Bros. Seed Co. v. Kalo Inoculant Co., 333 U.S. 127, 130, 76 USPQ 280, 281 (1948) (although claims 7, 8, 13 and 14 recited an inoculant comprising a bacterial mixture and a powder base, only the bacterial mixture was analyzed).
Performing the markedly different characteristics analysis comprises (a) selecting the appropriate naturally occurring counterpart(s) to the nature-based product limitation, (b) identifying appropriate characteristics for analysis, and (c) evaluating characteristics to determine whether they are “markedly different”.
Regarding step (a), the naturally occurring counterparts to the nature-based product, are the natural esophageal cells from esophageal tissues themselves (in vivo cells).
Regarding step (b), the appropriate characteristics for analysis include the phenotypes of esophageal cells from esophageal tissues (in vivo cells) compared to the claimed esophageal cells (in vitro cells).
Regarding step (c), in numerous instances the specification states that the in vitro produced cells are similar to those found in vivo (“In vitro cells are analogous to their in vivo counterparts and are enriched for basal cells” (paragraph [0034], referring to Fig. 5; “in vitro and in vivo esophagus share a high degree of molecular similarity”; paragraph [0037], referring to Fig. 8); “in vitro grown esophageal cells molecularly resemble basal and epibasal cell types from the native tissue” (paragraph [0038], referring to Fig. 9); “Benchmarking in vitro esophagus cultures to the in vivo reference using scRNA-seq showed that the basal stem cells were robustly maintained in vitro” (paragraph [0045]), “the data suggest that 2D expanded esophageal cells closely resemble the basal-epibasal cells observed in the human adult esophagus” (paragraph [0084], referring to Figs. 8 and 9).
Indeed, the specification does not point to any specific difference between in vitro or in vivo cells other than the distribution of specific cell types or markers (which are all still naturally occurring). However, this is due to culture conditions which are beyond the scope of the claims (see paragraph [0089], “in the low-density in vitro cell population, we see a statistically significant enrichment in TP63+ KRT4− cells when compared to the in vivo tissue . . . In the high-density culture, we observe a cellular distribution similar to that of the in vivo tissue”) and still demonstrates that in vitro and in vivo cells have the same markers.
Therefore, the specification indicates that the in vitro esophageal cells (the cells according to the method of claim 1) are not markedly different from those found in nature, and are themselves considered naturally occurring.
Accordingly, the claim is directed to an exception (Step 2A, prong one: YES).
In regard to Step 2A, prong two, the instant claims 21 and 22,
With respect to Step 2A, prong two, limitations that may be enough to qualify as additional elements that integrate the judicial exception into a practical application include:
Improvements to another technology or technical field.
Improvements to the functioning of the computer itself.
Applying the judicial exception with, or by use of, a particular machine.
Effecting a transformation or reduction of a particular article to a different state or thing
Adding a specific limitation other than what is well-understood, routine and conventional in the field, or adding unconventional steps that confine the claim to a particular useful application.
Other meaningful limitations beyond generally linking the use of the judicial exception to a particular technological environment.
With respect to Step 2A, prong two, limitations that were found not to be enough to qualify as additional elements that integrate the judicial exception into a practical application include:
Adding the words ‘‘apply it’’ (or an equivalent) with the judicial exception, or mere instructions to implement an abstract idea on a computer
Simply appending well-understood, routine and conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception, e.g., a claim to an abstract idea requiring no more than a generic computer to perform generic computer functions that are well understood, routine and conventional activities previously known to the industry
Adding insignificant extrasolution activity to the judicial exception, e.g., mere data gathering in conjunction with a law of nature or abstract idea
Generally linking the use of the judicial exception to a particular technological environment or field of use.
In regards to Step 2A, prong 2, claim 21 does not recite additional elements or a combination of elements in the claims other than the natural product itself. The claim is drawn only to a composition comprising expanded esophageal cell.
Regarding claim 22, while composition of expanded esophageal cells are part of a kit, the use of kits with cells is well understood, routine and conventional. For example, see Peng et al. (US 20070009437 A1), Claim 40, “A kit comprising: a) a mammalian cell”); Hsu et al. (WO 2004053097 A2), Claim 35, “A kit . . . comprising normal cells, tumor cells”); Fu et al. (WO 2014071157 A1), Claim 18, “A kit comprising a trans-differentiated or re-programmed cell” (that can be an esophageal cell, claim 5). (therefore, Step 2A, prong one: NO).
In regards to Step 2B, the claim does not recite additional elements that amount to significantly more than the judicial exception. In instant case, as above, regarding claim 21, claim is drawn only to a composition comprising expanded esophageal cell. Regarding claim 22, the claim on additionally requires that the cells are part of a kit. However, as above, kits with cells are well understood, routine and conventional, and as a whole this does not amount to more than the judicial exception. (therefore, Step 2B: NO).
Thus, claims 21 and 22 do not amount to significantly more than the judicial exception itself and do not qualify as patent eligible subject matter under 35 U.S.C. § 101.
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 (i.e., changing from AIA to pre-AIA ) 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, 6-15, and 21 are rejected under 35 U.S.C. 102(a)(1) or 35 U.S.C. 102(a)(2) as being anticipated by Xian (US20160237400, on IDS 06/15/2026) as evidenced by Belvins (Clinical Gastroenterology, 2018).
Regarding claim 1, Xian discloses a method for culturing esophageal cells in vitro for the expansion of those cells (claims 1 and 10; Abstract). Xian discloses that the esophageal cells are obtained from tissues (claim 10). Regarding the culturing steps. Xian discloses that cells are cultured in a growth medium (claim 1; paragraphs [0024, 0676]). A person of ordinary skill in the art would have realized that this requires placing the cells in a container and therefore, seeding them. Xian discloses that the growth medium comprises a mitogenic growth factor (e.g., EGF, specifically), a rho-kinase (ROCK) inhibiting agent, a Wnt agonist (a Wnt signaling pathway activating agent), a TGFβ receptor inhibitor, and a BMP inhibitor (BMP inhibiting agent) (claims 1 and 22; paragraphs [0045; 0678]).
Regarding claim 2, Xian discloses that the medium can comprise hydrocortisone, EGF, Y-276327, CHIR99021, A83-01, and noggin (claims 22, 30; paragraphs [0042, 0043, 0045, 0046, 0049]).
Regarding claim 3, Xian discloses that in some embodiments cells are preferentially cultured on a Matrigel that does not support 3-dimensional growth (claim 19; paragraph [0038]), which a person of ordinary skill in the art would have recognized infers that the cells are preferentially cultured in 2-dimension (i.e., are “2-dimensional esophageal cells” as interpreted above).
Regarding claim 6, Xian discloses that the esophageal cells can be esophageal stem cells (paragraph [0020]).
Regarding claim 7, Xian discloses that the esophageal cells can be fetal cells (paragraph [0017]).
Regarding claim 8, Xian discloses that the esophageal cells can be adult cells (paragraph [0017]).
Regarding claim 9, Xian discloses that the cells are dissociated by enzymatic digestion (paragraph [0034]). It is noted that the sentence “wherein prior to the culturing step the esophageal cells are minced or enzymatically digested” has not been interpreted literally (i.e., interpreting that the cells themselves are literally digested or minced), but rather as referring to the process of separating them from their tissues as discussed in the instant specification (paragraph [0080]).
Regarding claim 10, regarding the sentence, “wherein the expanded esophageal cells possess esophageal stem cells and/or differentiated esophageal cells” this has been interpreted to mean that the expanded esophageal cells comprise esophageal stem cells and/or differentiated esophageal cells. As above, Xian discloses that the esophageal cells can be esophageal stem cells (paragraph [0020]). Therefore, since these cells can be expanded the would necessarily comprise (possess) esophageal stem cells.
Regarding claim 11, Xian discloses that the cells can be frozen (cryopreserved) (paragraph [0062]).
Regarding claims 12 and 13, Xian discloses that frozen (cryopreserved) cells can be thawed (paragraph [0062]). Since these cells can be thawed and put into culture according to the methods of the invention without losing their characteristics (paragraph [0062]), they are considered capable of performing the intended use of being thawed “for purposes” of generation of esophageal cell lines or organoid tissue (see MPEP 2111.02, if the prior art structure is capable of performing the intended use, then it meets the claim).
Regarding claim 14, “wherein the expanded esophageal cells are stratified esophageal epithelium cells”, this is an inherent property of heathy esophageal epithelial cells. As evidenced by Blevins, esophageal cells are stratified squamous cells (Fig. 1, 609; see also instant paragraph [0004], as understood in the art, “The stratified epithelium of the esophagus is maintained throughout adulthood”). As above, Xian discloses that the cells are derived from esophagus (claims 1 and 10). Xian also teaches that the cells are epithelial cells and are healthy ([0094]). Therefore, the cells as disclosed by Xian are stratified esophageal epithelium cells.
Regarding claim 15, as above, the cells of Xian are stratified esophageal epithelium cells (see rejection of claim 14). Since Xian discloses preferred 2-dimensional embodiments, the expanded cells also comprise 2-dimensional stratified esophageal epithelium.
Regarding claim 21, Xian discloses compositions of the expanded cells (paragraph [0566]).
Therefore, Xian anticipates the invention as claimed.
Claim Rejections - 35 USC § 103
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 (i.e., changing from AIA to pre-AIA ) 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 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.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Xian (US20160237400, on IDS 06/15/2026) in view Thermo Fisher (Corning Costar Flat Bottom Cell Culture Plates, available online 07/24/2021, retrieved from WayBackMachine 09/16/2026).
Xian anticipates claim 1 as discussed above.
Regarding claim 4, regarding a 9.8 cm2, it is noted that this is close to the surface area of a typical 6-well plate (see Thermo Fisher, Specifications, first page, culture area of a Corning 3516, 6-well plate is 9.5 cm2; see MPEP 2144.05, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985)).
To this end, in embodiments, Xian teaches that cells can be cultured in 6-well plates. It would have been predictably obvious to use 9.8 cm2 plates because Xian indicates that in embodiments, 6-well plates (which have a similar size) are suitable for culturing cells epithelial cells (of which esophageal cells are a type).
Regarding the volume, as taught by Thermo Fisher, these dishes are designed to have a working volume of 2 to 3 mL (Specifications, second page), which overlaps with a volume of approximately 2 mL.
It would have been predicably obvious to use approximately 2 mL because 6-well plates are known to be used with these volumes. Furthermore, because as above, in embodiments Xian teaches that 6-well plates were used, it could have been done with predictable results and a reasonable expectation of success.
Regarding the generation of 2-dimensional expanded esophageal cells (interpreted to mean, in 2-dimensional conditions), discussed above, Xian teaches that in some embodiments cells are preferentially cultured on a Matrigel that does not support 3-dimensional growth (claim 19; paragraph [0038]), which a person of ordinary skill in the art would have recognized infers that the cells are preferentially cultured in 2-dimension (i.e., are “2-dimensional esophageal cells” as interpreted above) since in dishes cells can only be cultured in 2-dimension or 3-dimension.
Since the cells of Xian expand cells, performing the method of Xian in 2-dimensional conditions would results in “generation of 3-dimensional expanded esophageal cell”.
Therefore, the combined teachings of Xian and Thermo Fisher render the invention unpatentable as claimed.
Claims 5 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Xian (US20160237400, on IDS 06/15/2026) in view Thermo Fisher (Corning Costar Flat Bottom Cell Culture Plates, available online 07/24/2021, retrieved from WayBackMachine 09/16/2026) and Kasagi et al. (Cellular and Molecular Gastoenterology and Hepatology, 2018, on IDS 06/15/2026).
Xian anticipates claim 1 as discussed above.
Regarding claim 5, regarding a 9.8 cm2, it is noted that this is close to the surface area of a typical 6-well plate (see Thermo Fisher, Specifications, first page, culture area of a Corning 3516, 6-well plate is 9.5 cm2; see MPEP 2144.05, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985)).
To this end, in embodiments, Xian teaches that cells can be cultured in 6-well plates. It would have been predictably obvious to use 9.8 cm2 plates because Xian indicates that in embodiments, 6-well plates (which have a similar size) are suitable for culturing cells epithelial cells (of which esophageal cells are a type).
Regarding the volume, as taught by Thermo Fisher, these dishes are designed to have a working volume of 2 to 3 mL (Specifications, second page), which either overlaps with or is at least close to a volume of approximately 4 mL.
It would have been predicably obvious to use approximately 4 mL because 6-well plates are known to be used with volumes that overlap with or are at least close to this volume.
Furthermore, because as above, in embodiments Xian teaches that 6-well plates were used, it could have been done with predictable results and a reasonable expectation of success.
Regarding the generation of 3-dimensional expanded esophageal cells (interpreted to mean, in 3-dimensional conditions), discussed above, Xian teaches that in some embodiments cells are preferentially cultured on a Matrigel that does not support 3-dimensional growth (claim 19; paragraph [0038]).
In addition to suggesting 2-dimensional conditions, a person of ordinary skill in the art would have also understood that this also suggests 3-dimensional conditions as well (even if not preferred) since as above in culture dishes, cells can only be cultured under 2-dimensional or 3-dimensional conditions.
Regarding preferred embodiments, Applicant is directed to MPEP 2123, “The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain.” In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)).
A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Merck & Co. v.Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989).
Additionally, preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). “A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use.” In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994).
Regarding 3-dimensional conditions, it was long known in the art that esophageal cells could be cultured under 3-dimensional conditions.
A person of ordinary skill in the art would have been motivated to culture cells under 3-dimensional conditions, in order to produce organoids which can be used for personalized medicine, disease modeling, or test the effects of cell signaling in these tissues as taught by Kasagi (“We optimized culture conditions for 3-dimensional mouse and human esophageal organoids and used this experimental platform with potential applications toward personalized medicine to identify disruption of notch3 mediated squamous cell differentiation as a mechanism contributing to reactive epithelial changes under inflammatory conditions” (Summary, p333). Furthermore, because Kasagi teaches methods for culturing epithelial cells from tissues in 3-dimension (Fig. 1, p336), because Xian and Kasagi are in the same technical field of isolating and culturing esophageal cells from tissues, and because Xian suggests a 3-dimensional embodiments, a person of ordinary skill in the art could have utilized 3-dimensional conditions with the method of Xian with predicable results and a reasonable expectation of success.
Since the cells of Xian expand cells, performing the method of Xian in 3-dimensional conditions would results in “generation of 3-dimensional expanded esophageal cell”.
Regarding claim 16, as above, the cells of Xian are stratified esophageal epithelium cells (see rejection of claim 14). It would have been prima facie obvious to perform the method of Xian in 3-dimension as discussed above. Therefore, under 3-dimensional conditions, the expanded cells also comprise 3-dimensional stratified esophageal epithelium.
Therefore, the combined teachings of Xian, Thermo Fisher, and Kasagi render the invention unpatentable as claimed.
Claims 17 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Xian (US20160237400, on IDS 06/15/2026) in view of Ferrer-Torres et al. (bioRxiv, 05/20/2021, on IDS 06/15/2026) and Suprynowicz et al. (PLoS ONE, 2017, on IDS 06/15/2026).
Xian anticipates claim 1 as discussed above.
Regarding claims 17 and 18, Xian discloses the culturing comprises culturing cells on lethally irradiated 3T3-J2 (i.e., 3T3-J2i) feeder cells in the medium (claim 1; paragraphs [0017, 0035]). However, the use of both lethally and sub-lethally irradiated feeder cells was known in the art before the effective filing date. Specifically, Ferrer-Torres (who is noted is an inventor) teaches that human esophageal basal-stem cells can be maintained long-term on sub-lethally irradiated 3T3-J2i feeder cells (third page). As taught by Ferrer-Torres, they observed that the sub-lethally irradiated 3T3-J2i feeder cells do not proliferate, while esophageal cells continue to proliferate and can be passaged for at least 40 days (third page; referring also to Fig. 2). Additionally, Suprynowicz teaches that irradiated 3T3-J2 feeder cells (i3T3-J2 feeder cells, which are noted are sub-lethally irradiated) in combination with ROCK inhibitor Y267362 converts primary epithelial cells growing in vitro into an undifferentiated adult stem cell-like state that is characterized by long-term proliferation; maintains the proliferation of these cells from various tissues; and the cells retain their tissue-specific differentiation potential upon removal of the culture conditions (Abstract, p1). Therefore, it would have been prima facie obvious to substitute lethally irradiated 3T3-J2i feeder cells with sub-lethally irradiated 3T3-J2i. A person of ordinary skill in the art would have been motivated to do so because both Ferrer-Torres and Suprynowicz teach that sub-lethally irradiated 3T3-J2i promote long-term proliferation of primary cells, and because Ferrer-Torres teaches that esophageal cells specifically can proliferate long-term on these cells. Furthermore, because Ferrer-Torres teaches that esophageal cells can be proliferated on sub-lethally irradiated 3T3-J2i feeder cells, and teaches that this technique was already known in the art (“included sub-lethally irradiated 3T3-J2 feeder cells (X. Liu et al., 2017)”), a person of ordinary skill in the art could have substituted using lethally irradiated 3T3-J2 feeder cells with sub-lethally irradiated 3T3-J2 feeder cells with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Xian, Ferrer-Torres, and Suprynowicz render the invention unpatentable as claimed.
Claim 22 is rejected under 35 U.S.C. 103 as being unpatentable over Xian (US20160237400, on IDS 06/15/2026) in view of Fu et al. (WO2014071157A1).
Xian anticipates claim 1 as discussed above.
Regarding claim 22, Xian teaches that the invention provides kits and reagents for carrying out the methods of the invention (paragraph [0537]). Since the methods require esophageal cells to be carried out, it suggests that cells can be provided in the kits. Additionally, a person of ordinary skill in the art would have been motivated to formulate the expanded esophageal cells produced from the methods of claim 1 in a kit composition for delivery of those cells to other researches or institutes for use in applications such as in vitro assays or for tissue engineering. Furthermore, because Fu teaches kits can comprise esophageal cells (claims 1, 5, 13, and 18), a person of ordinary skill in the art could have included expanded esophageal cells produced from the methods of claim 1 in a kit with predicable results and a reasonable expectation of success.
Therefore, the combined teachings of Xian and Fu render the invention unpatentable as claimed.
Conclusion
No claims are allowed.
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/JOSEPH PAUL MIANO/Examiner, Art Unit 1631
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