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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 2/10/2026 has been entered.
Claims 1, 3, 19-20, 27-32 and 34 are pending in the instant application.
Terminal Disclaimers
On 2/10/2026 Applicants submitted two terminal disclaimers over US Patents 11674122 and 12324817. These terminal disclaimers were not approved for the following reason: The Applicant cited on the terminal disclaimer must be cited exactly as it is cited on the ADS and/or filing receipt, and also in its entirety. (The terminal disclaimers cite the applicant as “SHENZHEN ALPHA BIOPHARMACEUTICAL CO”, whereas the ADS and filing receipt cite the Applicant as “SHENZHEN ALPHA BIOPHARMACEUTICAL CO. LTD.”)
Applicants are advised that if they need more space for the “Applicant” section they can use a smaller font or submit an attachment page to the terminal disclaimer.
If Applicants correct and submit the terminal disclaimers no new fee is required.
Election/Restrictions
Applicants previously elected Group I, methods of regulating differentiation, dedifferentiation, transdifferentiation, aging and apoptosis of target cells by activating or inhibiting the JAK-STAT signaling pathway in target cells. Applicants further elected species of the method wherein:
the JAK-STAT signaling pathway is inhibited
the STAT5A and/or STAT5B gene is targeted, and
fibroblasts are the targeted cell type.
Due to the significant amendments to the claims, the only remaining relevant detail is: fibroblasts are the targeted cell type.
Claims 1, 3, 27-29 and 34 read on the elected invention and elected species. Claims 19-21 and 30-32 are withdrawn from consideration as being directed to non-elected invention and/or species.
Claim Interpretation
As amended, claim 1 is drawn to a method of regulating differentiation, dedifferentiation, transdifferentiation, rejuvenation, aging and apoptosis of fibroblasts, the method comprising:
treating the fibroblasts with only a small molecule mixture in a fibroblast culture medium,
wherein the small molecule mixture consists of a small molecule combination selected from [one of the five options recited].
The phrase “treating the [fibroblasts] with only a small molecule mixture in a fibroblast culture medium” is interpreted as meaning the method comprises a treatment step, and the treatment step consists of treating the [fibroblasts] with a fibroblast culture medium comprising a small molecule mixture, wherein the small molecule mixture consists of one of the five options recited.
While the “small molecule mixture” is limited to consisting of the five recited options, the “fibroblast culture medium” is not limited by the claim. There is no definition for “fibroblast culture medium” in the specification. Any cell culture medium capable of supporting fibroblasts will be considered to read on “fibroblast culture medium”. Additional molecules, including small molecules like water, amino acids, vitamins (beyond vitamin C), and carbohydrates must be present in a culture medium in order to supports fibroblasts (See, e.g. Yang, Z., & Xiong, H.-R. (2012). Culture Conditions and Types of Growth Media for Mammalian Cells. InTech. at Pg. 3-4 “1.1.1. Nutritional components”). This leads to confusion about what small molecules can be present in the medium, and what is excluded. A rejection is made under 35 USC 112(b) below.
For purposes of compact prosecution, the broadest reasonable interpretation of the claim will be that the fibroblast culture medium permits for additional chemicals, salts, proteins, and small molecules beyond those recited in the five options recited in the claim. Any additional agents will be considered part of the ‘fibroblast culture medium’, and thus not run afoul of the limited scope of ‘small molecule mixture’.
Status of Prior Rejections/Response to Arguments
RE: Rejection of claims 1, 3, and 27-29 under 35 USC 112(a), written description:
The amendment to claim 1 is effective to overcome the rejection of record. The specification does teach culturing fibroblasts in fibroblast cell culture medium containing the various small molecule combinations recited. The rejection is withdrawn.
RE: Rejection of claims 1, 3, and 27-29 under 35 USC 112(a), enablement:
The amendment to claim 1 is effective to overcome the rejections of record. Claim 1 now permits for inclusion of “fibroblast culture medium” in the method. “Fibroblast culture medium” is not defined in the specification, but is being understood to permit for any culture medium containing at least the minimum nutrients necessary to support fibroblast cell culture. The fibroblast culture medium is interpreted as being non-limited, and thus can include additional chemicals, salts, proteins, and small molecules beyond those recited in the five options recited in the claim. The rejection is withdrawn.
New Rejections
Claim Rejections - 35 USC § 112
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, 3, 27-29 and 34 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 claim 1: For reasons set forth above under claim interpretation, claim 1 is understood to include a step of treating fibroblasts in a fibroblast culture medium comprising a small molecule mixture, wherein the small molecule mixture is defined as consisting of one of the five recited combinations of small molecules.
There is no definition in the specification for “fibroblast culture medium”. Many culture media were known as appropriate for fibroblasts. The most basic/minimal culture medium appropriate for fibroblast cell culture is MEM, but the claim is not limited to the most basic/minimal culture medium appropriate for fibroblasts, rather it simply says “fibroblast culture medium”. Even MEM contains molecules that are considered small molecules, such as CaCl2, KCl, MgSO4, arginine, cystine, glucose, folic acid, inositol and thiamine (See Yang et al, “3.1.1. Basic components”). Given that even the most basic/minimal culture medium appropriate for fibroblasts contains small molecules beyond those recited in the five claimed combinations, it is unclear if/how the claim is restricting the small molecules present in the culture medium to only those recited in the five claimed combinations. It is unclear if additional components (including small molecules) can be present as part of the ‘fibroblast culture medium’ and not run afoul of the limitation that the ‘small molecule mixture consists of [the five recited combinations of small molecules].’
Claims 3, 27-29 and 34 depend from claim 1, inherit the deficiency, and are rejected on the same basis.
Regarding claim 34: Claim 34 is further rejected because it is unknown what “FibGro” is. It is appreciated that the specification refers to “FibGro medium (cat. No. FGS0040, rFib)”, but in a search of both the patent and non-patent literature, the term is only found in patent publications of the current application family, and patent publications of US Patent Application No 17/086397 and application family. The composition thereof is unknown. Therefore, the metes and bounds of the claim cannot be determined.
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.
Claims 1, 3 and 27-29 are rejected under 35 U.S.C. 103 as being unpatentable over Lu et al (US 2018/0055887).
Lu et al disclose generation of induced MSCs (iMSCs) from skin cells, e.g., fibroblasts, using a culture medium comprising at least a PKC inhibitor and/or a glycogen synthase 3 beta inhibitor (See ¶0009). The GSK3ß inhibitor can be, inter alia, CHIR99021 (See ¶0061). The PKC inhibitor can be, inter alia, Go6983 (See ¶0060).
The culture medium can further comprise auxiliary agents to enhance the efficacy of dedifferentiation/reprogramming of fibroblasts to iMSCs including:
JNK inhibitor, such as SP600125,
ROCK inhibitor, such as Y-27632
cAMP activator, such as forskolin [sic: froskolin],
HDAC inhibitor, such as VPA,
TGFß inhibitor, such as RepSox,
antioxidant, such as Vitamin C,
DOTIL inhibitors (See ¶0011).
EPZ004777 is disclosed as a DOTIL inhibitor (See ¶0071).
Table B lists additional suitable auxiliary agents, within Table B are also listed: TTNPB (See Pg 16) and 5-aza-CR (AZA), a DMNT inhibitor (See Pg 17).
In Example 1, Lu et al report differentiating human fibroblasts into iMSCs by culturing in DMEM plus a chemical cocktail (6C+3GF), including:
p38 inhibitor SB202190,
JNK inhibitor SP600125,
PKC inhibitor Go6983,
ROCK inhibitor Y-27632,
GSK3ß inhibitor CHIR99201,
LIF,
bFGF, and
TGFß
for six days (See ¶0238).
The method of Example 1 of Lu et al is comparable to the instant claims as follows:
Regarding claims 1 and 3: The method of Lu et al achieves differentiation of human fibroblasts to iMSCs. This reads on a method of regulating differentiation of target cells (the human fibroblasts being target cells). The medium comprises DMEM containing a chemical cocktail (6C + 3GF). The DMEM containing 6C + 3GF reads on a fibroblast culture medium. 6C + 3GF contains several chemicals which inhibit the JAK-STAT signaling pathway, specifically: ROCK inhibitor Y-27632. Only fibroblasts are treated in the culture.
Lu et al does not exemplify inclusion of RepSox, forskolin, vitamin C, and/or EPZ004777.
However, because each of RepSox, forskolin, vitamin C, and Epz004777 were disclosed as auxiliary agents that are beneficial for improving generation of the iMSCs, it would have been prima facie obvious to have included all of the auxiliary agents taught by Lu et al in the culture medium. The rationale for this conclusion of obviousness is that it is prima facie obvious to combine known prior art elements taught for the same purpose to achieve a predictable result. In this case, the predictable result would be improved differentiation of fibroblasts to iMSCs. The predictability is based on the teaching in Lu et al that each of the disclosed auxiliary agents are beneficial for achieving differentiation of fibroblasts to iMSCs.
Specifically, it would have been prima facie obvious to add into the culture medium comprising DMEM and the 6C + 3GF chemical cocktail exemplified in Example 1 a TGFß inhibitor, such as RepSox, and cAMP activator, such as forskolin, DOTIL inhibitor EPZ004777 (which is also a HMT inhibitor), and antioxidants, such as Vitamin C, thus meeting the limitations of the fourth species recited by amended claim 1. The additional small molecules and chemicals present are considered part of the ‘fibroblast culture medium’.
Regarding claim 27: Following the discussion of claim 1 above, Lu et al disclose suitable ranges of concentrations for each of the small molecules discussed above in Table B. The disclosed ranges substantially overlap and/or encompass the claimed ranges. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. See MPEP 2144.05.
Regarding claim 28: The source of the human fibroblasts (i.e. from skin) is a product-by-process limitation and does not affect the actual fibroblasts. However, Lu et al does use fibroblasts from human skin.
Regarding claim 29: Following the discussion of claim 1 above, Lu et al culture the human fibroblasts in the culture medium for six days, which falls within the claimed range of 24 hours to 220 days.
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.
Claims 1, 3, and 27-29 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of U.S. Patent No. 11674122.
Although the claims at issue are not identical, they are not patentably distinct from each other because the patented claims anticipate the instant claims.
Regarding claims 1 and 3: Patented claim 1 involves inducing human fibroblasts into MSCs. The fibroblasts are the target cells, and differentiation state of the cells is regulated. The method involves first pre-treating the fibroblasts with:
a lysine deacetylase inhibitor (which are also HDAC inhibitors),
an inhibitor of TGF-ß signaling pathway,
an activator of WNT/ß-catenin signaling pathway, and
an activator of cAMP signaling pathway; then
treating the fibroblasts with:
Repsox, an inhibitor of TGF-ß signaling pathway,
Go6983, an inhibitor of PKC signaling pathway,
CHIR99021, an inhibitor of WNT/ß-catenin signaling pathway,
forskolin, an activator of the cAMP signaling pathway,
VPA, a lysine deacetylase inhibitor (also an HDAC inhibitor),
TTNPB and AM580, each activators of RA signaling pathway,
EPZ004777, an HMT inhibitor
Y-27632, a ROCK inhibitor, and
ascorbic acid (vitamin C).
Each of the Repsox, Go6983, CHIR99021, forskolin, VPA, TTNPB, AM580, EPZ004777 and Y-27632 are inhibitors of the JAK-STAT pathway; thus the patented method serves to regulate differentiation of target cells by inhibiting the JAK-STAT pathway. The combination of small molecules used in the second treating step anticipates the second and fourth combinations recited in instant claim 1. As the patented claims successfully culture fibroblasts, the patented method necessarily also reads on a fibroblast culture medium. Any small molecules and/or chemicals beyond those recited in the second and fourth combinations of claim 1 are considered part of the fibroblast culture medium.
Regarding claim 27: Following the discussion of claim 1 above, the patented claims do not teach the concentration of the various agents, but generally differences in concentration are considered prima facie obvious, absent evidence of criticality. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. See MPEP 2144.05.
Regarding claim 28: The source of the human fibroblasts (i.e. from skin) is a product-by-process limitation and does not affect the actual fibroblasts.
Regarding claim 29: Patented claim 29: Patented claim states the second treating step occurs for 6-10 days, which is within the scope of 24 hrs to 220 days.
Claims 1, 3, 27-29 and 34 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 9, 16 and 21-32 of US Patent No. 12324817.
Although the claims at issue are not identical, they are not patentably distinct from each other because the copending claims anticipate and/or render obvious the instant application.
Regarding claims 1, 29 and 34: Patented claims 1 and 7 are each drawn to methods of preparing rejuvenated and regenerative fibroblasts by treating target cells with a first and second composition. This reads on rejuvenation of target cells. The methods of each of claims 1 and 7 involve first treating the target cells with: HG-DMEM supplemented with 10% FBS,
a Wnt/ß-catenin agonist CHIR99021,
an HDAC inhibitor VPA,
a cAMP agonist forskolin, and
a TGF-ß inhibitor RepSox; then
treating the cells with:
HG-DMEM supplemented with 10% FBS,
a Wnt/ß-catenin agonist CHIR99021,
an HDAC inhibitor VPA,
a cAMP agonist forskolin,
a TGF-ß inhibitor RepSox,
a RAR agonists AM580 and TTNPB,
a HMT inhibitor EPZ004777,
ascorbate (vitamin C (Vc)),
PKC inhibitor Go-6983,
ROCK inhibitor Y-27632, and
a JNK inhibitor SP600125.
The HG-DMEM plus 10% FBS reads on a fibroblast growth medium, specifically that of claim 34. The combination of small molecules used in the second treating step anticipates the first, second, and fourth combinations recited in instant claim 1. The patented claims state the second treating step occurs for 7 days, which is within the range of claim 29.
Regarding claim 3: Patented claim 12 states the fibroblasts are from a human.
Regarding claim 27: Patented claims 5-6 disclose concentrations for each of the small molecules . The disclosed concentration either anticipate and/or render obvious the amounts required by instant claim 27, specifically noting that, generally differences in concentration are considered prima facie obvious, absent evidence of criticality. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. See MPEP 2144.05.
Regarding claim 28: The source of the human fibroblasts (i.e. from skin) is a product-by-process limitation and does not affect the actual fibroblasts.
Examiner Comment
If the terminal disclaimers were corrected and approved, then the following amendment to claim 1 would place claims 1, 3, and 27-29 into condition for allowance:
1. A method of regulating differentiation, dedifferentiation, transdifferentiation, rejuvenation, aging and apoptosis of target cells, comprising:
treating the target cells with a composition consisting of high glucose DMEM (HG-DMEM) supplemented with fetal bovine serum (FBS), and
wherein the target cells are fibroblasts,
the small molecule mixture consists of a small molecule combination selected from the group consisting of:
Valproic acid (VPA), CHIR99021, Repsox, Forskolin, SP600125, Go 6983, Y-27632, Vitamin C (Vc), TTNPB, AM580 and EPZ004777;
VPA, CHIR99021, Repsox, Forskolin, Go 6983, Y-27632, Vc, TTNPB, AM580 and EPZ004777;
Ruxolitinib and S3I-201;
Y-27632, Vc, EPZ004777, Forskolin and Repsox; and
VPA, CHIR99021, Repsox, Forskolin, Go 6983, Y-27632, AM580 and EPZ004777, Vc, TTNPB and 5-Aza-2’-deoxycytidine.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALLISON M FOX whose telephone number is (571)272-2936. The examiner can normally be reached M-F 10-6 EST.
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/ALLISON M FOX/Primary Examiner, Art Unit 1633
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