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 .
Claim Status
Claims 1-10 are pending.
Claims 9-10 are withdrawn.
Claims 1-8 are under examination.
Election/Restrictions
Applicant’s election with traverse of the following invention
Invention
Group I, claims 1-8, drawn to a culture medium for hepatoma organoid, in the reply filed on 4th, August, 2026 is acknowledged.
Applicant traverses on the grounds stated below, which are not persuasive for the reasons stated below.
Applicant traverses on the grounds that “while Group I claims are directed to a culture medium for hepatoma organoid, Group II and Group III claims are directed to methods using compounds according to claim 1. Thus, as Groups I-III include the same culture medium, they are clearly related to each other as aspects of a single inventive concept” (pg. 3).
Applicant further traverses on the grounds that “search for a culture medium as delineated in claim 1 would inevitably function to find art pertaining to methods for their use. As provided, the search burden is substantially minimized by the existing overlap of the claims of Groups I-III” (pg. 3).
In response, this is not found persuasive for several reasons. First, instant claims are drawn to a product and two methods, which are not one of the allowed combinations of inventions. The PCT rules provide for the examination of the first claimed product, the first claimed method of making that product, and the first claimed method of using that product in one application, but do not provide for the examination of multiple products or unrelated methods (see 37 CFR § 1.475(a)-(d)).
Next, the Lack of Unity previously set forth does not allege that there is no shared inventive concept, but rather alleges that the technical feature fails to make a contribution over the prior art as set forth previously.
Applicant further traverses on the grounds that “the PCT Rules, which are the governing provisions in the instant case, specifically permit product claims and process of use claims to be examined together in one application” (pg. 4).
In response, while Applicant references searches, undue search burden are not a criteria for election/restriction purposes under 35 USC §121 and 35 USC § 372 and therefore this is not found persuasive.
Applicant further traverses on the grounds that “Liu et al. is disqualified as a reference under the exception provided under 35 U.S.C. §102(b)(2)(C)” (pg. 5).
In response, this is not found persuasive because while U.S.C. §102(b)(2)(C) applies to overcoming prior art for rejections which use art under U.S.C. §102 or U.S.C. §103, this exception does not apply to art that is used to show a lack of Unity of Invention.
It is additionally noted that Applicant’s statement concerning common ownership also does not meet the requirements to disqualify the Liu reference. Specifically, Applicant is directed to MPEP 717.02 (a) which states that In order to invoke common ownership to except a disclosure as prior art, the applicant (or the patent owner) must provide a statement that the disclosure of the subject matter on which the rejection is based and the claimed invention were owned by the same person or subject to an obligation of assignment to the same person not later than the effective filing date of the claimed invention. The statement should either be on or begin on a separate sheet and must not be directed to other matters (37 CFR 1.4(c) ). The statement must be signed in accordance with 37 CFR 1.33(b). In the instant case, the statement is made together with response to the restriction requirement and is therefore directed to other matters. There is an additional document provided with the response on a separate sheet with information on the patent assignment of the Liu reference. This is also insufficient because this document does not include the required statement that the disclosure of the subject matter on which the rejection is based and the claimed invention were owned by the same person or subject to an obligation of assignment to the same person not later than the effective filing date of the claimed invention, and is also not signed in accordance with 37 CFR 1.33(b).
Furthermore, it is additionally noted that Applicant has not contested the reasons for obviousness of the technical feature set forth by the combination of Liu et al. (US-20230235283-A1; Published 17th, October 2024 with priority to 8th, July, 2021; henceforth “Liu”), Huch Ortega et al. (US-10597633-B2; henceforth “Huch Ortega”), and Endo et al. (J Thorac Oncol. 2013 Feb;8(2):131-9.; henceforth “Endo”) as set forth in the Lack of Unity.
The requirement is still deemed proper and is therefore made FINAL.
Claims 9-10 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Priority
The instant Application was filed on 8th, March, 2024, is a 371 of PCT/CN2021/118657 filed on 16th, September, 2021 and claims priority to CHINA 202111048845.4 filed on 8th, September, 2021.
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows: The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of the first paragraph of 35 U.S.C. 112. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e).
Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Thus the instant claims are being given the filing date of PCT/CN2021/118657 filed on 16th, September, 2021.
Objections to Abstract
Trade Name or Marks used in Commerce
The abstract is objected to because it uses the term “B27” (line 2) and GlutaMAX (line 4) which is a trade name or mark used in commerce that is not accompanied by the generic terminology and does not include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Appropriate correction is Required.
Objections to the Specification
Trade Name or Marks used in Commerce
The use of the terms B27, GlutaMAX, DMEM, RPMI, Matrigel, and Primocin, which are trade names or marks used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Objections to Specification
The disclosure is objected to because of the following informalities:
Pg. 11 has the following figure embedded into the specification:
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Drawings must be presented on one or more separate sheets. They may not be included in the description, the claims or the abstract (see MPEP 1825 and 37 CFR 1.437)
Appropriate correction is required.
Claim Objections
Claims 1 and 6 are objected to because of the following informalities:
Claim 1 recites the preamble of “a culture medium for hepatoma organoid” which is missing an article between “for” and “hepatoma.”
Claim 6 is missing a conjunction (such as “and”) between the last two listed conditions.
Appropriate correction is required.
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 1-8 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites the trademarked term “B27,” and “GlutaMAX” and claim 7 recites the trademarked terms “DMEM/F12” (which included the trademarked term DMEM), “DMEM,” “RPMI-1640” (which contains the trademarked term RPMI) and “Primocin”
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 cell culture additive and, accordingly, the identification/description is indefinite.
Because this reagent was developed by the manufacturer at the time of the applicant’s invention under the trade names and as a result is proprietary, which means what constitutes as B27, GlutaMAX, DMEM, RPMI or Primocin can change, and these changes do not need to be disclosed by these companies to the public. Accordingly, the identification of the trade name is indefinite and the applicant is advised to employ a sequence, the SeqID, IUPAC name and/or CAS number for this agent.
MPEP 2173.05(u) states that if 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 the 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph. Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). See also Eli Lilly & Co. v. Apotex, Inc., 837 Fed. Appx. 780, 784-85, 2020 USPQ2d 11531 (Fed. Cir. 2020).
Regarding the status of B27, DMEM, and RPMI as trademarks, Applicant is directed to MPEP 608.01(v) which defines a trademark as follows:
The term "trademark" includes any word, name, symbol, or device, or any combination thereof-
(1) used by a person, or
(2) which a person has a bona fide intention to use in commerce and applies to register on the principal register established by this chapter,
to identify and distinguish his or her goods, including a unique product, from those manufactured or sold by others and to indicate the source of the goods, even if that source is unknown.
Although the Trademarks for DMEM (number 98618988), B27 (number 77129891) and RPMI (number 78115891) are dead/abandoned, they still meet the definition of a trademark according to the MPEP because they are each a term “which a person has a bona fide intention to use in commerce” “to identify and distinguish his or her goods.” Since the trademark Application was filed (i.e. “applies to register on the principal register” MPEP 608.01(v) above), it falls under the definition of a trademark, even if the Trademark Status is now Dead/Abandoned.
Accordingly, for the reasons stated above, the claims are indefinite due to the presence of the trademark terms.
By nature of their ultimate dependency on claim 1, claims 2-8 are also rejected because they do not clarify the issue.
Claim 7 recites the term “initial medium,” while the instant specification is silent to a definition of the phrase “initial medium.” The scope of claim 7 is indefinite because the term “initial” suggests a timing, while the claim is drawn to a single medium. The metes and bounds of the structure of the claims is indefinite because it is unclear whether the mediums recited in claim 7 are required at a particular timing and it is unclear how that structure would be incorporated into the composition of instant claims.
Claim 8 recites “free of Wnt agonists, R-spondin family proteins, Noggin proteins, BMP inhibitors, or fibroblast growth factor 10.” which is a negative limitation together with a list of alternative embodiments. The presence of negative limitation together with a list of alternative embodiments makes it unclear whether the negative limitation applies to all of the listed options, or whether it applies to the listed options in the alternative.
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.
Claims 1-8 are rejected under 35 U.S.C. 103 as being obvious over Liu et al. (US-20230235283-A1; Published 17th, October 2024 with priority to 8th, July, 2021; henceforth “Liu”) in view of Huch Ortega et al. (US-10597633-B2; henceforth “Huch Ortega”), and Endo et al. (J Thorac Oncol. 2013 Feb;8(2):131-9.; henceforth “Endo”).
Regarding claim 1, Liu discloses: a primary cell culture medium comprising an MST 1/2 Kinase Inhibitor of Formula I (claims 1-5)
B27 additive and/or N2 additive (para. [0019]);
hepatocyte growth factor (para. [0019]);
an ITS cell culture additive (Tables 3, 9; para. [0108]),
Y27632 (Tables 3-6, 9; para. [0003-0004, 0017, 0021, 0058, 0097-0101, 0108, 0115, 0124, 0129, 0173]; claim 1; Figures 12, 13D, 13G),
Insulin (ITS includes insulin; Tables 3, 9; para. [0108]),
an epidermal cell growth factor (Figures 3C; Tables 3, 6-7; para. [0019, 0097, 0108, 0113, 0122, 0129]; claims 8-9),
and non-essential amino acids (Table 5).
However, regarding claim 1, although Liu teaches the cell culture media is for primary epithelial cells (ESCC cells) Liu is silent to including dexamethasone, insulin supplement, and GlutaMAX in the cell culture medium.
Nevertheless, regarding claim 1, Huch Ortega teaches cell culture medium for primary epithelial cells (primary epithelial stem cells) to expand the cells and obtain an organoid (abstract) that includes dexamethasone (col. 3-4, 19, 33-36, 64, 67, 74, 82, 86; claims 7, 9, 36 and 38) insulin supplement (col. 18, 38, 48, 72) and GlutaMAX (col. 33, 38) in the culture medium. Huch Ortega teaches the method using the medium is relevant to the culture of all epithelial cell types (col. 2).
Therefore, regarding claim 1, it would have been obvious to a person of ordinary skill in the art to prepare the cell culture media of Liu, and combine the known prior art elements of the dexamethasone, insulin supplement, and GlutaMAX of Huch Ortega to obtain the predictable result of a cell culture medium. One of ordinary skill would have been motivated to do so as taught by Huch Ortega to expand the cells and obtain an organoid (abstract) and because Huch Ortega teaches the method using the medium is relevant to the culture of all epithelial cell types (col. 2). Regarding the reasonable expectation of success, Huch Ortega evidences preparation of cell culture mediums including dexamethasone (col. 3-4, 19, 33-36, 64, 67, 74, 82, 86; claims 7, 9, 36 and 38) insulin supplement (col. 18, 38, 48, 72) and GlutaMAX (col. 33, 38).
Regarding claim 1, although Liu teaches the medium is for epithelial cancer cells (ESCC cells), Liu and Huch Ortega are silent to including Neuregulin-1 in the culture medium.
Nevertheless, regarding claim 1, Endo teaches that including Neuregulin-1 in cell culture medium potently induces growth of cancer epithelial cells (CTOS; “consisted of epithelial cell adhesion molecule (EpCAM)–positive epithelial cells” pg. 133) (abstract; pg. 136 “Neuregulin 1 Stimulated CTOS Growth In Vitro”).
Therefore, regarding claim 1, it would have been obvious to a person of ordinary skill in the art to prepare the cell culture medium suggested by Liu in view of Huch Ortega, and combine the known prior art element of the Neuregulin 1 of Endo to obtain the predictable result of a cell culture medium. One of ordinary skill would have been motivated to do so as taught by Endo to induce growth of the cells. Regarding the reasonable expectation of success, Endo evidences preparation of culture media including Neuregulin-1 (abstract; Methods; pg. 136 “Neuregulin 1 Stimulated CTOS Growth In Vitro”).
Regarding the preamble of claim 1, the preamble merely states, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction (see MPEP 2111.02) See also Rowe v. Dror, 112 F.3d 473, 478, 42 USPQ2d 1550, 1553 (Fed. Cir. 1997) ("where a patentee defines a structurally complete invention in the claim body and uses the preamble only to state a purpose or intended use for the invention, the preamble is not a claim limitation"). In the instant case, Liu in view of Huch Ortega and Endo suggest all the required structural elements of the complete invention in the claim body and therefore the meets instant claims. Furthermore, because Liu in view of Huch Ortega and Endo teach a cell culture medium comprising the claimed components, it is capable of meeting the recited intended use of “for hepatoma organoid.”
Regarding claim 2, further to the discussion of claim 1 above, Liu teaches
R1 is selected from C1 -C6 alky 1, C3-C6 cycloalky 1, C4-C8 cycloalky lalky 1, C2-C6 spirocycloalkyl, and phenyl optionally substituted with 1-2 independent R6, naphthyl optionally substituted with 1-2 independent R6, phenylmethyl optionally substituted with 1-2 independent
R6 and thienyl optionally substituted with 1-2 independent R6;
R2 and R3 are each independently selected from C1-C3 alkyl;
R4 and R5 are each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl,
C4-C8 cycloalkylalkyl, hydroxyl C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkylamino C1-C6 alkyl,
C1-C6 alkoxy C1-C6 alkyl, piperidyl C1-C6 alkyl, and tetrahydropyranyl C1-C6 alkyl;
R6 is selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl (para. [0008-0016]; claims 1-5).
Regarding claim 3, further to the discussion of claim 1 above, Liu teaches the MST1/2 kinase inhibitor comprises a compound of Formula (Ia) or a pharmaceutically acceptable salt, or a solvate thereof wherein, R1 is selected from C1-C6 alkyl, phenyl optionally substituted with 1-2 independent R6,
thienyl optionally substituted with 1-2 independent R6, and phenylmethyl optionally substituted
with 1-2 independent R6; R5 is selected from hydrogen, C1-C6 alky 1, and C3-C6 cycloalkyl;
R6 is independently selected from halogen, C1-C6 alkyl, and C1-C6 haloalkyl (para. [0016]; claims 3 and 5).
Regarding claim 4, further to the discussion of claims 1 and 3 above, Liu teaches R1 is phenyl optionally substituted with 1-2 independent R6; R5 is hydrogen; R6 is fluoro, methyl or trifluoromethyl (claim 4; para. [0015-0016]).
Regarding claim 5, further to the discussion of claim 1 above, Liu teaches the compounds labeled from 1 to 59 as the MST1/2 kinase inhibitor (para. [0016]; claim 5).
Regarding claim 6, further to the discussion of claim 1 above, Liu teaches
the concentration of the MST1/2 kinase inhibitor is 2 to 6 μM , which overlaps with the claimed 2.5-10 μM (para. [0018]; claim 6);
the volume ratio of the B27 or N2 cell culture additive in the culture medium is 1:25-1:50 which lies within the claimed 1:25-1:100 (claim 9);
the concentration of the hepatocyte growth factor is 10 ng/ml-20 ng/ml which lies within the claimed 1-25 ng/mL (claim 9);
the concentration of Y27632 is 7.5 μM-12.5 μM which lies within the claimed 3-30 μM (claim 7).
Regarding claim 6, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. See M.P.E.P. §2144.05. Therefore, because the taught ranges of MST1/2 kinase inhibitor, volume ratio of the B27 or N2, hepatocyte growth factor, and Y27632 overlap or lie within the claimed ranges, a prima facie case of obviousness exists.
Additionally, regarding claim 6, Applicant is reminded that generally, differences in concentration will not support patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical (MPEP 2144.05 II).
Regarding claim 7, further to the discussion of claim 1 above, Liu teaches the medium comprises DMEM/F12, DMEM, F12 (para. [0026, 0028, 0090, 0094-0095, 0099, 0103, 0107, 0109, 0146, 0167, 0179]; Table 1, 3, 5-7, 9; Example 2) or RPMI-1640 (para. [0030]; Table 2); and
an antibiotic selected from streptomycin/penicillin, amphotericin B and Primocin (para. [0028, 0034]; Table 1, 6).
Regarding claim 8, further to the discussion of claim 1 above, Liu teaches the culture medium is free of Wnt agonists, R-spondin family proteins or BMP inhibitors (claim 10).
Hence, the claimed invention as a whole was prima facie obvious.
Examiner’s Remark
Because the prior art of Liu et al. (US-20230235283-A1; Published 17th, October 2024 with priority to 8th, July, 2021; henceforth “Liu”) was applied in the Lack of Unity mailed on 5th, June, 2026, for the sake of compact prosecution, arguments considered pertinent to the grounds of rejection are addressed below.
Response to Arguments
Applicant’s arguments, filed 4th, August, 2026, have been fully considered but are not found persuasive.
Applicant argues “Liu et al. is disqualified as a reference under the exception provided under 35 U.S.C. §102(b)(2)(C)” (pg. 4).
In response, this is not found persuasive because Applicant has not met the criteria to disqualify the Liu reference under 35 U.S.C. §102(b)(2)(C).”
Specifically, Applicant is directed to MPEP 717.02 (a) which states that In order to invoke common ownership to except a disclosure as prior art, the applicant (or the patent owner) must provide a statement that the disclosure of the subject matter on which the rejection is based and the claimed invention were owned by the same person or subject to an obligation of assignment to the same person not later than the effective filing date of the claimed invention. The statement should either be on or begin on a separate sheet and must not be directed to other matters (37 CFR 1.4(c) ). The statement must be signed in accordance with 37 CFR 1.33(b). In the instant case, the statement is made together with response to the restriction requirement and is therefore directed to other matters. There is an additional document provided with the response on a separate sheet with information on the patent assignment of the Liu reference. This is also insufficient because this document does not include the required statement that the disclosure of the subject matter on which the rejection is based and the claimed invention were owned by the same person or subject to an obligation of assignment to the same person not later than the effective filing date of the claimed invention, and is also not signed in accordance with 37 CFR 1.33(b).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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/apply/applying-online/eterminal-disclaimer.
Non-Statutory Double Patenting
U.S. Co-pending Application No. 17918971
Claims 1-8 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 and 14-15 of U.S. Co-pending Application No. 17918971 (claims set filed 25th, February, 2026) in view of in view of Huch Ortega et al. (US-10597633-B2; henceforth “Huch Ortega”), and Endo et al. (J Thorac Oncol. 2013 Feb;8(2):131-9.; henceforth “Endo”).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
It is noted that U.S. Co-pending Application No. 17918971 has had a notice of Allowance mailed on 27th, May, 2026. When the Application is allowed, this rejection will no longer be provisional and will be an actual Non-Statutory Double Patenting rejection.
The subject matter claimed in the instant application is disclosed in the referenced application as follows the primary cell culture medium makes obvious the primary cell culture medium of the instant application.
Although the claims at issue are not identical, they are not patentably distinct for the reasons stated below.
Regarding claim 1, U. S. Co-pending App ‘971 claims a cell culture media comprising an MST1/2 kinase inhibitor of Formula (I) or a pharmaceutically acceptable salt, or a solvate thereof; at least one cell culture additive selected from N2 and B27; a hepatocyte growth factor, an ITS cell culture additive, Y27632, and an epidermal cell growth factor (claim 1).
However, regarding claim 1, although U. S. Co-pending App ‘971 claims the cell culture media is for primary epithelial cells (ESCC cells) (claim 1), U. S. Co-pending App ‘971 does not claim dexamethasone, insulin supplement, amino acids and GlutaMAX in the cell culture medium.
Nevertheless, regarding claim 1, Huch Ortega teaches cell culture medium for primary epithelial cells (primary epithelial stem cells) to expand the cells and obtain an organoid (abstract) that includes dexamethasone (col. 3-4, 19, 33-36, 64, 67, 74, 82, 86; claims 7, 9, 36 and 38) insulin supplement (col. 18, 38, 48, 72) amino acids (column 38 and 40 and one of ordinary skill would at once envisage “non-essential amino acids from the limited genus of “amino acids”) and GlutaMAX (col. 33, 38) in the culture medium. Huch Ortega teaches the method using the medium is relevant to the culture of all epithelial cell types (col. 2).
Therefore, regarding claim 1, it would have been obvious to a person of ordinary skill in the art to prepare the cell culture media as claimed by U. S. Co-pending App ‘971 and combine the known prior art elements of the dexamethasone, insulin supplement, amino acids, and GlutaMAX of Huch Ortega to obtain the predictable result of a cell culture medium. One of ordinary skill would have been motivated to do so as taught by Huch Ortega to expand the cells and obtain an organoid (abstract) and because Huch Ortega teaches the method using the medium is relevant to the culture of all epithelial cell types (col. 2). Regarding the reasonable expectation of success, Huch Ortega evidences preparation of cell culture mediums including dexamethasone (col. 3-4, 19, 33-36, 64, 67, 74, 82, 86; claims 7, 9, 36 and 38) insulin supplement (col. 18, 38, 48, 72), amino acids (column 38 and 40) and GlutaMAX (col. 33, 38).
However, regarding claim 1, although U. S. Co-pending App ‘971 claims the medium is for epithelial cancer cells (ESCC cells), U. S. Co-pending App ‘971 does not claim and Huch Ortega is silent to including Neuregulin-1 in the culture medium.
Nevertheless, regarding claim 1, Endo teaches that including Neuregulin-1 in cell culture medium potently induces growth of cancer epithelial cells (CTOS; “consisted of epithelial cell adhesion molecule (EpCAM)–positive epithelial cells” pg. 133) (abstract; pg. 136 “Neuregulin 1 Stimulated CTOS Growth In Vitro”).
Therefore, regarding claim 1, it would have been obvious to a person of ordinary skill in the art to prepare the cell culture medium as claimed by U. S. Co-pending App ‘971 in view of Huch Ortega, and combine the known prior art element of the Neuregulin 1 of Endo to obtain the predictable result of a cell culture medium. One of ordinary skill would have been motivated to do so as taught by Endo to induce growth of the cells. Regarding the reasonable expectation of success, Endo evidences preparation of culture media including Neuregulin-1 (abstract; Methods; pg. 136 “Neuregulin 1 Stimulated CTOS Growth In Vitro”).
Regarding the preamble of claim 1, the preamble merely states, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction (see MPEP 2111.02) See also Rowe v. Dror, 112 F.3d 473, 478, 42 USPQ2d 1550, 1553 (Fed. Cir. 1997) ("where a patentee defines a structurally complete invention in the claim body and uses the preamble only to state a purpose or intended use for the invention, the preamble is not a claim limitation"). In the instant case, the cell culture medium as claimed by U. S. Co-pending App ‘971 in view of Huch Ortega and Endo suggests all the required structural elements of the complete invention in the claim body and therefore the meets instant claims and is capable of meeting the recited intended use of “for hepatoma organoid.”
Regarding claim 2, further to the discussion of claim 1 above, U. S. Co-pending App ‘971 claims R1 is selected from C1-C6 alkyl, C3-C6 cycloalkyl, C4-C8 cycloalkylalkyl, C2-C6 spirocycloalkyl, and phenyl optionally independently substituted with 1-2 R6, naphthyl optionally 2 independently substituted with 1-2 R6, phenylmethyl optionally independently substituted with 1- 2 R6 and thienyl optionally independently substituted with 1-2 R6; R2 and R3 are each independently selected from C1-C3 alkyl; R4 and R5 are each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C4-C8 cycloalkylalkyl, hydroxyl C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkylamino C1-C6 alkyl, C1-C6 alkoxy C1-C6 alkyl, piperidyl C1-C6 alkyl, and tetrahydropyranyl C1-C6 alkyl; R6 is selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl (claim 2).
Regarding claim 3, further to the discussion of claim 1 above, U. S. Co-pending App ‘971 claims the MST1/2 kinase inhibitor comprises a compound of Formula (Ia) or a pharmaceutically acceptable salt, or a solvate thereof wherein R1 is selected from C1-C6 alkyl, phenyl optionally independently substituted with 1-2 R6, thienyl optionally independently substituted with 1-2 R6, and phenylmethyl optionally independently substituted with 1-2 R6; R5 is selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl; R6 is independently selected from halogen, C1-C6 alkyl, and C1-C6 haloalkyl (claim 3).
Regarding claim 4, further to the discussion of claims 1 and 3 above, U. S. Co-pending App ‘971 claims R1 is phenyl optionally substituted with 1-2 independent R6; R5 is hydrogen; R6 is fluoro, methyl or trifluoromethyl (claim 4).
Regarding claim 5, further to the discussion of claim 1 above, U. S. Co-pending App ‘971 claims the MST1/2 kinase inhibitor is compounds 1 to 59 or a pharmaceutically acceptable salt thereof (claim 5).
Regarding claim 6, further to the discussion of claim 1 above, U. S. Co-pending App ‘971 claims
the concentration of the MST1/2 kinase inhibitor is 0.75 to 6 μM which overlaps with the claimed 2.5-10 μM (claim 14);
the volume ratio of the B27 or N2 cell culture additive in the culture medium is 1:25 to 1:50 which lies within the claimed 1:25-1:100 (claim 14);
the concentration of the hepatocyte growth factor is 10-20 ng/mL which lies within the claimed 1-25 ng/mL (claim 14); and
the concentration of Y27632 is 2.5 to 15 μM which lies within the claimed 3-30 μM (claim 14).
Regarding claim 6, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. See M.P.E.P. §2144.05. Therefore, because the claimed ranges of MST1/2 kinase inhibitor, volume ratio of the B27 or N2, hepatocyte growth factor, and Y27632 overlap or lie within the claimed ranges, a prima facie case of obviousness exists.
Additionally, regarding claim 6, Applicant is reminded that generally, differences in concentration will not support patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical (MPEP 2144.05 II).
Regarding claim 7, further to the discussion of claim 1 above, Huch Ortega teaches basal mediums to be used including DMEM, DMEM/F12 and F12 as well as RPMI-1640 (col. 33, 38, 59-60 and Example 12). Huch Ortega teaches the basal medium may also include penicillin/streptomycin (col. 38), and it would therefore be obvious to combine these known prior art elements of Huch Ortega with a reasonable expectation of success for the same reasons set forth above (see claim 1 rejection above) to expand the cells and obtain an organoid and because Huch Ortega teaches the method using the medium is relevant to the culture of all epithelial cell types (col. 2).
Regarding claim 8, further to the discussion of claim 1 above, U. S. Co-pending App ‘971 claims the culture medium is free of Wnt agonists, R-spondin family proteins, or BMP inhibitors.
Since instant Application claims are obvious over cited Application claims, in view of Huch Ortega and Endo, said claims are not patentably distinct.
Pertinent Co-Pending Applications
The following co-pending Applications are made of record because they are pertinent to Applicant’s disclosure but are not relied upon for a rejection.
U.S. Co-pending Application Nos 18577457, 18692569, 17927530 and 18700796 each claim cell culture medias comprising an MST1/2 kinase inhibitor identical to the instantly claimed Formula (I) as well as a method of culturing using the medium and a method of screening using the medium. Each of the claimed cell culture medias recites an intended use of a specific cell type.
U.S. Co-pending Application No. 18577457
U. S. Co-pending App ‘457 (claim set filed 22nd, July, 2026) claims a cell culture media comprising an MST1/2 kinase inhibitor of Formula (I) or a pharmaceutically acceptable salt, or a solvate thereof; at least one cell culture additive selected from N2 and B27; a hepatocyte growth factor; and Y27632 (claim 1).
U. S. Co-pending App ‘457 does not claim the required elements of instant Application claims of an ITS cell culture additive, dexamethasone, Neuregulin-1, insulin, an epidermal cell growth factor, GlutaMAX, and non-essential amino acids and these are not fairly taught or suggested by the prior art.
U.S. Co-pending Application No. 18692569
U. S. Co-pending App ‘569 (claim set filed 15th, March, 2024), claims a cell culture media comprising an MST1/2 kinase inhibitor of Formula (I) or a pharmaceutically acceptable salt, or a solvate thereof; at least one cell culture additive selected from N2 and B27; an epidermal cell growth factor and Y27632 (claim 1).
U. S. Co-pending App ‘569 does not claim the required elements of instant Application claims of a hepatocyte growth factor, an ITS cell culture additive, , dexamethasone, Neuregulin-1, insulin, GlutaMAX, and non-essential amino acids and these are not fairly taught or suggested by the prior art.
U.S. Co-pending Application No. 18700796
U. S. Co-pending App ‘796 (claim set filed 12th, April, 2024) claims a cell culture media comprising an MST1/2 kinase inhibitor of Formula (I) or a pharmaceutically acceptable salt, or a solvate thereof; at least one cell culture additive selected from N2 and B27; an ITS cell culture additive, Y27632, insulin and an epidermal cell growth factor (claim 1).
U. S. Co-pending App ‘796 does not claim the required elements of instant Application claims of a hepatocyte growth factor; dexamethasone, Neuregulin-1, GlutaMAX, and non-essential amino acids and these are not fairly taught or suggested by the prior art.
U.S. Co-pending Application No. 17927530
U. S. Co-pending App ‘530 (claim set filed 3rd, February, 2026) claims a cell culture media comprising an MST1/2 kinase inhibitor of Formula (I) or a pharmaceutically acceptable salt, or a solvate thereof; a hepatocyte growth factor, an ITS cell culture additive, Y27632, and insulin (as ITS complex) (claim 1).
U. S. Co-pending App ‘530 does not claim the required elements of instant Application claims of at least one cell culture additive selected from N2 and B27; dexamethasone; Neuregulin-1; an epidermal cell growth factor, GlutaMAX, and non-essential amino acids and these are not fairly taught or suggested by the prior art.
Pertinent Art
The following prior art made of record but not relied upon is considered pertinent to Applicant’s disclosure.
Triastuti
Triastuti et al. (Br J Pharmacol. 2019 Oct 8;176(20):3956–3971.; henceforth “Triastuti”) discloses a cell culture media comprising an MST1 kinase inhibitor (XMU-MP-1 cultured 72 hours with “the addition of XMU‐MP‐1 at 1–5 μM” pg. 3958 col. 1 3rd para.).
Liu2
Liu et al. (WO-2020073906-A1; see IDS filed 8th, March, 2024; see also attached English Translation; henceforth “Liu2”) discloses a pharmaceutical composition comprising an MST kinase inhibitor of the following structure:
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346
163
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(abstract; claims;)
Which encompasses embodiments of the instantly claimed Markush structure of Formula (I), copied below for reference.
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231
268
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(from instant claim 1).
The MST kinase inhibitor structure disclosed by Liu comprises the structure of Formula (I) of instant claim 1 where:
R1 (of instant claims, R4 of Liu reference) is selected from C1-C6 alkyl, C3-C6 cycloalkyl, C4-C8 cycloalkylalkyl, C2-C6 spirocycloalkyl, heteroaryl, or aryl (claims; pg. 1);
R2 and R3 (of instant claims, R2 and R3 of Liu reference) are each independently selected from Cl-C6 alkyl (claims);
R4 and R5 (of instant claims, R5 and R6 of Liu reference) are each independently selected from hydrogen, C1- C6 alkyl, C3-C6 cycloalkyl, C4-C8 cycloalkylalkyl, C3-C6 heterocycloalkyl, C1 -C6 alkylamino C1-C6 alkyl, C1-C6 alkoxy Cl-C6 alkyl, and C3-C6 heterocyclyl Cl-C6 alkyl (claims) (see also specifically recited structures in the tables which recite specific structures within the claimed Markush).
Liu2 discloses the composition comprises Ringer’s injection or lactated Ringer’s injection.
Hoffman
Hoffman et al. (WO-2003020722-A1; citations refer to attached translation; henceforth “Hoffman”) teaches dihydropteridinones of formula (I)
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266
438
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wherein R1 is a radical selected from the group consisting of hydrogen, NH, XH, halogen and a C 1 -C 3 -alkyl group which is optionally substituted by one or more halogen atoms,
R is a radical selected from the group consisting of hydrogen, CHO, XH, -X-C 1 -C 2 -alkyl and an optionally substituted CrC 3 -alkyl group,
R3 , R4 are identical or different , a radical selected from the group consisting of optionally substituted C 1 -C 8 -alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, aryl, Heteroaryl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl, -X-aryl, -X-heteroaryl, -X-cycloalkyl, -X-heterocycloalkyl, -NR 8 -aryl, -NR 8 -heteroaryl, -NR 8 -cycloalkyl, and -NR 8 heterocycloalkyl, or a radical selected from the group consisting of hydrogen, halogen, COXR 8 , CON (R 8 ) 2) COR 8 and XR 8 ,
or R 3 and R 4 together form a 2- to 5-membered alkyl bridge which can contain 1 to 2 heteroatoms,
R5 is hydrogen or a radical selected from the group consisting of optionally substituted Cι-Cι 0 alkyl, C 2 -C10 alkenyl, C 2 -C 10 alkynyl, aryl, heteroaryl and -C 3 -C 6 cycloalkyl,
or R3 and R5 or R4 and R5 together form a saturated or unsaturated C 3 -C 4 alkyl, which may contain 1 to 2 heteroatoms,
R6 optionally substituted aryl or heteroaryl,
R7 is hydrogen or -CO-XC 1 -C 4 alkyl, and X each independently of one another, O or S,
R8 selected each independently, hydrogen or a radical from the group consisting of optionally substituted C1-C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 -alkynyl and phenyl, if appropriate in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, and if appropriate their pharmacologically acceptable acid addition salts (claim 1 and Description; see in particular Table 1).
Embodiments of the structure of Hoffman are encompassed by the structure of Formula (I) of instant claims (see claim 1 and table 1).
Hoffman teaches a composition comprising a cell culture media (F12 medium) and the dihydropteridinones (“active substances were added to the cells”) for cancer cells (cervical carcinoma tumor cell line HeLaS3) (pg. 109 7th para.).
Conclusion
No claim is allowable.
Correspondence
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/BRIANA N EBBINGHAUS/Examiner, Art Unit 1632
/EMILY A CORDAS/Primary Examiner, Art Unit 1632
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