DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s Response to Election/Restriction Filed, Amendment, and Arguments/Remarks, filed 22 July 2026, have been entered. Claims 1-6, 12-16, 18-22, 24-25, 27, and 30 were previously pending in the application. Applicants canceled claims 2-3, 5-6, 21-22, 24-25, 27, and 30 and added new claims 31-35. Claims 1, 4, 12-16, 18-20, and 31-35 are currently pending. Claims 1, 12, and 15 are independent claims.
Applicants’ election with traverse of the invention of Group I, drawn to a composition, a kit, and a culture medium, is acknowledged.
Applicant’s traversal argues that the present claims share a special technical feature of the use of a RA pathway activator, a GSK-3 inhibitor, and an IKK signaling pathway inhibitor which is shared across the identified Groups I and II (claims 3, 6, 15-16, and 18-20; claims 3 and 6 now canceled) and, accordingly, the instant claims satisfy the unity of invention criteria in that Deng does not teach or suggest the use of an IKK signaling pathway inhibitor. Applicant further argues that the ability to induce totipotency in a pluripotent cell is a nonobvious result which is not portended by the cited art.
However, this is not agreed.
The special technical feature shared by the Groups I and II is anticipated by the prior art of Deng [US20190282624Al, published 19 September 2019] as set forth on p. 4 of the previous office action. The amended claims filed by Applicants on 22 July 2026 does not provide evidence that the previously filed claims of 24 July 2024 share a special technical feature over the prior art of Deng et al. (2019) and that the standard for restriction under 35 U.S.C. 121 and 372 has thus been improperly applied.
Moreover, note that the ability to achieve totipotency is not a shared technical feature of Groups I and II. The shared technical feature, according to the amended claims filed 22 July 2026, amounts to a composition comprising an RA signaling pathway activator, a GSK3 inhibitor, and an IKK signaling pathway inhibitor.
Deng was cited for teaching a composition or kit comprising one least one of each of (a) a retinoic acid (RA) signaling pathway activator which is a retinoic acid receptor agonist (including TTNPB); and (b) a glycogen synthase kinase (GSK) inhibitor (including a GSK-3 inhibitor CHIR99021), a TGFβ receptor inhibitor; a cyclic AMP (cAMP) agonist, an S-adenosylhomocysteine hydrolase (SAH) inhibitor, histone acetylator (including the HDAC inhibitor valproic acid), a DOTIL methyltransferase inhibitor, an epigenetic modulator, and an inhibitor of histone demethylation [0009, 0051, 0090-0091, claim 1]. However, Applicant amended the claims to specifically require an IKK pathway inhibitor in addition to the RA signaling pathway activator and the GSK3 inhibitor.
McLean [US20220192984A1, published 23 June 2022, filed 02 October 2019] discloses a composition comprising a retinoic acid signaling pathway activator (i.e., retinoic acid receptor agonists) [0191, 0242, 0974, 1812, Table 1, 13]; a GSK3 inhibitor [0002, 0201, 0205]; and the ErbB3/HER3 inhibitor WS6 [0310-0312, Table 25], wherein Shen teaches that the compound WS6 inhibits both the Erb3 binding protein 1 (EBP1) pathway and the IKK pathway [Shen et al. 2013, Journal of the American Chemical Society, 135, 1669-1672, abstract, pg 1670 col 2 ¶ 2- pg 1671 col 1 ¶ 1, pg 1671 col 2 ¶ 1, Figure 5]. As such, the shared technical feature does not make a contribution over the prior art. Accordingly, the shared technical feature is not a special technical feature and a unity of invention does not exist between Groups I and II. Accordingly, the requirement is still deemed proper is therefore made FINAL.
Claims 15-16 and 18-20 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. Please note that after a final requirement for restriction, the Applicants, in addition to making any response due on the remainder of the action, may petition the Commissioner to review the requirement. Petition may be deferred until after final action on or allowance of claims to the invention elected, but must be filed no later than appeal. A petition will not be considered if reconsideration of the requirement was not requested. (See § 1.181.)
Claims 1, 4, 12-14, and 31-35 are currently pending in the application and under examination to which the following grounds of rejection are applicable. An action on the merits follows.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/CN2022/115235, filed 26 August 2022, which claims priority to CHINA 202110989429.8, filed 26 August 2021, and CHINA 202210654031.1, filed 09 June 2022. Filing of a certified untranslated copies of the CHINA 202110989429.8, filed 26 August 2021, and CHINA 202210654031.1, filed 09 June 2022, is acknowledged.
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 earliest possible priority for the instant application is 26 August 2021.
Information Disclosure Statement
The information disclosure statements filed 26 February 2024, 19 November 2025, and 22 July 2026 have been considered by the Examiner.
Specification
The disclosure is objected to because of the following informalities: the Brief Description of the Drawings does not include a description of each panel. Specifically, the descriptions of Figure 9.1 a-d and 10 a-k does not include individual descriptions of panels 9.1a-d and 10a-k. See MPEP 608.01(f), which states, “When there are drawings, there shall be a brief description of the several views of the drawings and the detailed description of the invention shall refer to the different views by specifying the numbers of the figures, and to the different parts by use of reference letters or numerals”. Further, MPEP 608.01(f) instructs Examiners such that “If the drawings show Figures 1A, 1B, and 1C and the brief description of the refers only to Figure 1, the examiner should object to the brief description, and require applicant to provide a brief description of Figures 1A, 1B, and 1C.” Appropriate correction is required.
The use of the terms “DMEM” on pages 6, 36, 53, 54, 63, 64, “Knockout” on pages 6, 36, 52, 53, 63, 64, “DMEM/F12” on page 6, 36, 54, 73, “Bio-Rad CFX384 Real-Time PCR System” on page 55, “GlutaMAX” on page 61, 73, “Triton-X100” on page 62, “KSOM” on page 67, 73, which are trade names or a marks used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore, the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
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.
Note that the specification has not been inspected sufficiently to identify all instances of trade names and/or marks used in commerce. It is Applicant’s responsibility to ensure complete compliance.
Claim Objections
Claims 4, 33, and 34 are objected to because of the following informalities:
Claim 4 recites, “Tretionin” which appears to be a typographical misspelling of “Tretinoin”. Appropriate correction is required.
Claims 4, 33, and 34 are each dependent on independent claim 1 and each recite, “GSK-3”, which is inconsistent with the “GSK3” abbreviation presented in i claim 1. 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 4, 14, and 32 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 4 recites, “such as” in lines 2, 5, 7-8. Claim 14 recites, “such as” in line. Claim 32 also recites, “such as” in lines 2, 4-5, 6, 8, and 10. The phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 4 also recites, “Tretionin/RA/ATRA”, which is indefinite because it is unclear whether Tretionin, RA, and ATRA are meant to be synonyms or alternative options.
As such, the metes and bounds of the claims cannot be determined.
Claim 14 is in improper Markush form; a Markush group should be in the form “the basal culture medium selected from the group consisting of A, B, and C”. Currently, it is not clear which species are included in the Markush group and which are not.
Claim 14 also contains the trademark/trade name “DMEM”, “Knockout DMEM”, and “DMEM/F12” in lines 2 and 3. 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 basal media and, accordingly, the identification/description is indefinite.
As such, the metes and bounds of the claim cannot be determined.
Claim Interpretation
In the interest of compact prosecution, claims 4 and 32 have been interpreted such that the limitations following the term “such as” are exemplary and not required limitations of the claimed invention.
Claim 31 recites, “one or more of… and…” in lines 1-2, which has been interpreted such that the claim requires one or more components selected from the recited list and not one or more of each component recited. For example, the composition merely further comprising a single HDAC inhibitor will satisfy the claim without the composition also comprising a histone methyl transferase inhibitor, a Src kinase inhibitor, a cAMP activator, and a cell metabolism modulator.
Claim 32 recites further limitations to the option of claim 31 without requiring selection of any particular option. As such, the limitations of claim 32 apply only to the option(s) of claim 31 which are actually selected for any individual embodiment of the claimed invention. For example, if the composition further comprises only an HDAC inhibitor according to claim 31, then claim 32 only requires that the HDAC inhibitor be a small molecule.
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 therefore, subject to the conditions and requirements of this title.
Claims 1, 4, and 31-33 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature without significantly more. The claim(s) recite(s) a composition comprising (a) a retinoic acid (RA) signaling pathway activator; (b) a glycogen synthase kinase 3 (GSK3) inhibitor; and (c) an Ikappaβ kinase (IKK) signaling pathway inhibitor. Note that the composition is claimed by functional limitations. As such, any substance which is capable of the recited function meets the claimed structure.
The composition is not distinct from its naturally occurring counterpart because naturally occurring animal cells comprise retinoic acid (RA) signaling pathway activators, glycogen synthase kinase 3 (GSK3) inhibitors, and Ikappaβ kinase (IKK) signaling pathway inhibitors. For example, human cells comprise retinoic acid, which activates retinoic acid signaling pathway [Thompson et al. 2019, Human Genomics, 13(61), 1-15, abstract]; Akt, which inhibits GSK-3 [Medina & Wandosell 2011, International Journal of Alzheimer’s Disease, 2011, 479249, 1-12, pg 2 col 2 ¶ 4], and Iκβ, which inhibits the IKK signaling pathway [Israel 2010, Cold Spring Harbor Perspectives in Biology, 2, a000158, 1-15, pg 1 col 1 ¶ 1].
Dependent claim 4 further recites wherein the RA signaling pathway activator, GSK-3 inhibitor, and IKK signaling pathway inhibitor are small molecules, which is also indistinguishable from a product of nature. For example, grape plants comprise both β-carotene (an RA signaling pathway activator) [Pinho et al. 2001, J. Agric. Food Chem., 49, 5484-5488, abstract, pg 5484 col 1 ¶ 1; Thompson pg 2 col 2 ¶ 2-pg 4 col 1 ¶ 2, Figure 1] and resveratrol (which is both a GSK3 inhibitor and an IKK signaling pathway inhibitor) [Shin et al. 2009, Molecular Pharmacology, 76, 884-895, abstract; Ren et al. 2013, Pharmazie, 68, 689-694, abstract].
Dependent claims 31-32 further recite wherein the composition comprises a small molecule HDAC inhibitor, histone methyltransferase inhibitor, Src kinase inhibitor, cAMP activator, or cell metabolism modulator, which is also indistinguishable from a product of nature. Gonzalez-Abuin teaches that grape plants further comprise procyanidins which modulate glucose homeostasis and nutrient-induced GLP-1 secretion [Gonzalez-Abuin eta l. 2014, Am. J. Physiol. Cell. Physiol., 306, C485-C492, abstract].
Regarding dependent claim 33, Pinho further teaches wherein grapes comprise 519 µg/kg of β-carotene in the pulp, which corresponds to about 0.97 µM β-carotene in the pulp given a molecular weight of β-carotene of 536.9 g/mol and an approximate density of grape pulp of 1 g/mL corresponding to the density of water [Table 2]. Wang teaches wherein resveratrol is present in grape skins and leaves at variable concentrations, including at a concentration of 0.02 µg/g in grape skins for cultivar 1, which corresponds to about 0.088 µM resveratrol in the skin given a molecular weight of resveratrol of 228.25 g/mol and an approximate density of grape skin of 1 g/mL corresponding to the density of water [Wang et al. 2013, PLOS One, 8(4), e61642, 1-8, Table 2].
Therefore, the composition of claims 1, 4, and 31-33 are not distinct from a naturally occurring animal cell and/or grape plant.
This judicial exception is not integrated into a practical application because the claim merely recites a composition comprising the three components without any additional limitations. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims do not recite additional elements beyond those comprised within a naturally occurring cell/organism.
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.
Claim(s) 1, 4, 12, and 31-32 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zielinski [US20160331707A1, published 17 November 2016]; as evidenced by Batie et al. [2013, Bioorganic & Medicinal Chemistry, 21, 693-702]; Shin et al. [2009, Molecular Pharmacology, 76, 884-895]; Ren et al. [2013, Pharmazie, 68, 689-694]; Devi et al. [2018, Journal of Applied Pharmaceutical Science, 8(04), 150-160]; Aliomrani et al. [2016, DARU Journal of Pharmaceutical Sciences, 24(15), 1-8]; and Rahmani et al. [2015, Pharmacognosy Reviews, 9(18), 120-126].
Regarding claim 1, Zielinski discloses a composition comprising (a) a retinoic acid (RA) signaling pathway activator (i.e., β-carotene, retinol, or curcumin) [0073-0074, 0078-0080, 0143, claim 62, 80], (b) a glycogen synthase kinase 3 (GSK3) inhibitor (i.e., ferulic acid and resveratrol) [0076, 0142-0144, claim 62], and (c) an Ikappaβ kinase (IKK) signaling pathway inhibitor (i.e., phloretin and resveratrol) [0076, 0142-0144, claim 62].
Zielinski does not explicitly teach wherein curcumin are retinoic acid signaling pathway activators, ferulic acid and resveratrol are GSK3 inhibitors, nor wherein phloretin and resveratrol is an IKK signaling pathway inhibitor. However, note that the recited functions are inherent properties of the recited components. “When the structure recited in the reference is substantially identical to that of the claims, claimed properties or functions are presumed to be inherent.” See MPEP 2112.01 or In re Best, 195 USPQ 430, 433 (CCPA 1997). There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003).
Further, Batie teaches wherein curcumin and tetrahydrocurcumin activate retinoic acid pathway signaling by increasing RAR- and RXR-mediated gene expression [abstract, pg 695 col 2 ¶ 2, Figure 3]. Shin teaches wherein resveratrol inhibits GSK3 [abstract]. Devi teaches that ferulic acid inhibits GSK3 [abstract, pg 154 col 2 ¶ 2, pg 156 col 1 ¶ 1- pg 157 col 2 ¶ 1, pg 158 col 1 ¶ 1- col 2 ¶ 1, pg 158 col 2 /pp1- pg 159 col 1 ¶ 1]. Ren teaches wherein resveratrol inhibits IKK signaling pathway [abstract]. Aliomrani teaches that phloretin is an IKK inhibitor [pg 5 col 2 ¶ 2].
Regarding claim 4, the β-carotene, retinol, ferulic acid, and phloretin taught by Zielinski are all small molecules.
Regarding claim 12, Zielinski teaches testing the composition of the invention in cell culture, thereby teaching a cell culture medium comprising the composition of claim 1 [0083, 0142-0143, 0173-0174].
Regarding claims 31-32, Zielinski teaches the additional inclusion of small molecule metabolic modulators such as aloe vera extract, lactoferrin, or glucose oxidase [0103]. Although Zielinski does not teach specifically that these components are metabolic modulators, note that modulating metabolic functions are inherent properties of the recited components. For example, Rahmani teaches that small molecules (i.e., phytosterols) present in aloe vera extract reduce fasting blood glucose levels [pg 123 col 2 ¶ 2-3].
Accordingly, by teaching all the limitations of claims 1, 4, 12, and 31-32 as written, Zielinski anticipates the instant invention as claimed.
Claim Rejections - 35 USC § 102/103
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)(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.
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(s) 1, 4, 12, 31-32 are rejected under 35 U.S.C. 102(a)(2) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over McLean [US20220192984A1, published 23 June 2022, filed 02 October 2019, with priority to US 62/739,933, filed 02 October 2018]; as evidenced by and/or in view of Shen et al. [2013, Journal of the American Chemical Society, 135, 1669-1672].
Regarding claim 1, McLean discloses a composition comprising a retinoic acid signaling pathway activator (i.e., retinoic acid receptor agonists) [0191, 0242, 0974, 1812, Table 1, 13]; a GSK3 inhibitor [0002, 0201, 0205]; and the ErbB3/HER3 inhibitor WS6 [0310-0312, Table 25]. McLean does not teach wherein WS6 is an IKK signaling pathway inhibitor.
However, Shen teaches that the compound WS6 inhibits both the Erb3 binding protein 1 (EBP1) pathway and the IKK pathway [abstract, pg 1670 col 2 ¶ 2- pg 1671 col 1 ¶ 1, pg 1671 col 2 ¶ 1, Figure 5].
Therefore, McLean teaches the limitations of independent claim 1. Alternatively, to the extent that McLean does not explicitly recite the specific selection of one or more each of a RAR agonist, a GSK3 inhibitor, and an IKK signaling pathway inhibitor, then given the teachings of McLean to select from among a finite number of options of otic therapeutic agents which include each of the categories of agents recited in instant independent claim 1, and ordinarily skilled artisan at the time of filing the instant application would have been motivated to select a combination comprising one or more each of a RAR agonist, a GSK3 inhibitor, and an IKK signaling pathway inhibitor as an otic therapeutic composition.
Regarding claim 4, as described above, McLean teaches small molecules RAR agonist., a GSK3 inhibitors, and an IKK signaling pathway inhibitors [0002, 0191, 0201, 0205, 0242, 0310-0312, 0974, 1812, Table 1, 13, 25].
Regarding claim 12, McLean teaches determining the therapeutically effective amount initially in cell culture assays, thereby teaching a culture media comprising the composition of claim 1 [0792].
Regarding claims 31-32, McLean teaches wherein the composition further comprises the small molecule HDAC inhibitor valproic acid [0011-0012, 0014].
Regarding claim 34, McLean also teaches the inclusion of retinoic acid signaling pathway inhibitor TTNBP [0191, 0974, 1812, Table 1, 2]; the GSK-3 inhibitor 1-Azakenpaullone [Table 6, 15]; and the IKK signaling pathway inhibitor WS6 [0310-0312, Table 25].
Accordingly, by teaching all of the limitations of claims 1, 4, 12, 31-32, and 34, McLean anticipates the instant invention as claimed.
Alternatively, given the motivation taught by McLean to select a combination comprising one or more each of a RAR agonist, a GSK3 inhibitor, and an IKK signaling pathway inhibitor/ErbB3/HER3 inhibitor WS6 as an otic therapeutic composition, wherein the options include TTNPB, 1-Azakenpaullone, and WS6; and the teachings of McLean to test the compositions on cells in culture; it would have been prima facie obvious to an ordinarily skilled artisan at the time of filing the instant application to select a combination comprising one or more each of the RAR agonist TTNBP, the GSK3 inhibitor 1-Azakenpaullone, and the IKK signaling pathway inhibitor WS6 from the finite options presented by McLean and to include the composition within a culture media with a reasonable expectation of success.
Claim Rejections - 35 USC § 103
Claims 13-14, 33 and 35 are rejected under 35 U.S.C. 103 as being unpatentable over McLean [US20220192984A1, published 23 June 2022, filed 02 October 2019, with priority to US 62/739,933, filed 02 October 2018]; in view of Shen et al. [2013, Journal of the American Chemical Society, 135, 1669-1672]; as applied to claims 1, 4, 12, 31-32, and 34 above; and further in view of Hu [US20210205369A1, published 8 July 2021]; Meyers et al. [2012, Neural Development, 7(30), 1-18]; and Zhang et al. [2018, European Journal of Neuroscience, 48(10), 3299-3316].
As discussed above, McLean discloses a composition comprising the retinoic acid signaling pathway activator (i.e., retinoic acid receptor agonists) TTNPB [0191, 0242, 0974, 1812, Table 1, 13]; the GSK3 inhibitor 1-Azakenpaullone [0002, 0201, 0205]; and the ErbB3/HER3 inhibitor WS6 [0310-0312, Table 25], wherein Shen teaches that WS6 is also an IKK signaling pathway inhibitor [abstract, pg 1670 col 2 ¶ 2- pg 1671 col 1 ¶ 1, pg 1671 col 2 ¶ 1, Figure 5].
Regarding claims 13-14, Mclean teaches determining the therapeutically effective amount initially in cell culture assays, thereby teaching a culture media comprising the composition of claim 1 [0792] but does not explicitly teach wherein the culture media comprises a basal media which is DMEM®, Knockout DMEM®, RPMI 1640, or DMEM®/F12.
However, the use of basal media is a universal standard for culturing cells in vitro. For example, Shen teaches growing R7T1 β cells in supplemented DMEM® [supplemental information pg S1 ¶ 1]. Hu teaches growing the Fib and rFib cells in supplemented DMEM® or in a MSC basal medium [0149-0154, 0211, 0222-0223, Figure 45, 47]. Meyers teaches culturing embryos in supplemented E2 medium [pg 15 col 1 ¶ 3]. Zhang teaches culturing mouse fibrocytes in supplemented DMEM® [pg 4 ¶ 4] and culturing cochleae in supplemented DMEM®/F12 media [pg 5 ¶ 5- pg 6 ¶ 1, pg 7 ¶ 1]. Therefore, given the teachings of Shen, Hu, Meyers, and Zhang to successfully culture cells in supplemented basal media, such as supplemented DMEM® or DMEM®/F12, the ordinarily skilled artisan at the time of filing the instant application would have been motivated to use a basal medium, such as DMEM® or DMEM®/F12, in the culture of cells to assess the efficacy of the composition of claim 1 as taught by McLean.
Regarding claims 33 and 35, McLean teaches wherein the GSK-3 inhibitor CHIR99027 is present at a concentration ranging from 0.025 mg/ml to about 25 mg/ml, which corresponds to about 50 µM to about 50 mM given a molecular weight of CHIR99027 of 501.8 g/mol, or less than about 7.5 mg/mL (less than about 14.9 mM) [0036, 0041, 0046, 1603, claim 105]. McLean also teaches wherein 3 mM CHIR99027 is a concentration which is several hundred-fold above the active in vitro concentration [00845]. McLean also teaches wherein the CHIR99027 concentration in the cochlea within 0.5 hours of administration was 3.5 µM [00845].
McLean does not teach wherein the TTNPB concentration is 0.2 µM, wherein the 1-Azakenpaullone concentration is 2.5 µM, nor wherein the WS6 concentration is 0.5 µM.
Hu teaches using TTNPB in cell culture applications at a concentration of 0.2-20 µM or specifically 0.2 µM or 5 µM, wherein the small molecule composition comprising 0.2 µM TTNPB was effective to prepare regenerative fibroblasts (rFib) [0054, 0205, Table 1]. Therefore, given the teaching of McLean to determine the therapeutically effective amount initially in cell culture assays and the teachings of Hu to use a concentration of 0.2-20 µM TTNPB in cell culture, wherein 0.2 µM was an effective dose, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to use a range of TTNPB concentrations which encompass 0.2 µM to assess the therapeutically effective amount of TTNPB.
Meyers teaches assessing a dose response to 1-Azakenpaullone for embryos in culture, wherein a concentration of 2.5 µM was determined the be the minimum concentration tested which provided the full effect of blocking GSK3β activity to prevent eye formation [pg 2 col 2 ¶ 2]. Therefore, given the teachings of Meyers to test a series of concentrations of 1-Azakenpaullone in culture to examine the dose response to 1-Azakenpaullone, wherein 2.5 µM was determined to be the optimal working concentration, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to similarly use a series of concentrations to assess the dose response effects in culture to assess the effective amount of the drug in cell culture applications as taught by McLean; in so doing, the ordinarily skilled artisan would be motivated to include a dose of 2.5 µM given the teaching of Meyers that 2.5 µM is an effective dose for inhibiting GSK3β activity to prevent eye formation.
Zhang teaches that 0.5 µM WS6 is effective for enhancing MYO7+ cell generation and enhancing supporting cell proliferation in vitro in cell culture [Figure 7]. Therefore, given the teachings of Zhang that 0.5 µM WS6 is an effective dose in cell culture, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to use or at least test a dose of 0.5 µM WS6 when using WS6 in cell culture applications.
Given the motivation taught by McLean, Shen, Hu, Meyers, and Zhang to use a basal medium, such as DMEM® or DMEM®/F12, in the culture of cells to assess the efficacy of a composition in vitro; the motivation taught by McLean and Hu to use a range of TTNPB concentrations which encompass 0.2 µM to assess the therapeutically effective amount of TTNPB; the motivation taught by McLean and Meyers to include a dose of 2.5 µM in a series of concentrations assessing the therapeutically effective dose of TTNPB; and the motivation taught by Zhang to use or at least test a dose of 0.5 µM WS6 when using WS6 in cell culture applications; it would have been prima facie obvious for an ordinarily skilled artisan at the time of filing the instant application to modify the composition of McLean such that the culture media comprises a DMEM basal media and such that the composition comprises 0.2 µM TTNPB, 2.5 µM 1-Azakenpaullone, and 0.5 µM WS6 with a reasonable expectation of success.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Dr. KATIE L PENNINGTON whose telephone number is (703)756-4622. The examiner can normally be reached M-Th 8:30 am - 5:30 pm, Friday 8:30 am - 12:30 pm CT.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maria G. Leavitt can be reached on (571) 272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
DR. KATIE L. PENNINGTON
Examiner
Art Unit 1634
/KATIE L PENNINGTON/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
Prosecution Insights