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 . Claims 38, 40-74 filed December 09, 2025 are currently pending.
Status of Claims
As indicated in the Office Action of 09/16/2025, claims 52-74 were withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 07/11/2025.
Response to Amendment
Applicant’s amendments, filed 12/09/2025 are acknowledged. Claims 39 has been canceled in its entirety. Applicant has incorporated the limitations of claim 39 into independent claim 38. No new matter has been added.
Withdrawn Rejection(s)
In view of Applicant’s amendments to claim 38, the pending 35 U.S.C 102(a)(1) rejection of record over claims 38, 42-51 by Beebe is withdrawn.
Applicant's arguments, 12/09/2025 have been fully considered. Rejections and/or objections not reiterated from the previous Office Action are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set of rejections and objections presently being applied to the instant application.
Claim Rejections - 35 USC § 103-Rejection Maintained
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim(s) 38, 40-51 are rejected under 35 U.S.C. 103 as being unpatentable over the combination of Thabut (Hepatology Vol. 54 pages 573-585 published 2011), Wilhelm (Nature Review Drug Discovery Vol. 5 pages 835-845 published 2007), Iwaisako (PNAS Vol. 111 pages E3297-E3305 published 2014) and Beebe (Cancer Research Vol. 63 pages 7301-7309. Published 2003).
Thabut (Hepatology Vol. 54 pages 573-585 published 2011) teaches treating bile duct ligated liver fibrosis in a subject in need comprising administering a therapeutically effective amount of sorafenib. As shown in Figures 1-2, administration of a 1.5 mg/kg dose of sorafenib to patients with bile duct ligated liver fibrosis resulted in the inhibition of vascular remodeling as well as attenuated liver stiffness and matrix depositions in the fibrosis patient (abstract, page 575 left col. to right col., Figures 1 and 2).
Wilhelm (Nature Review Drug Discovery Vol. 5 pages 835-845 published 2007) teaches sorafenib is a potent inhibitor of multiple kinases including VEGF (Table 1, page 842 right col.) Wilhelm also teaches that sorafenib inhibits VEGFR2 with an IC50 of 90 nm and inhibits downstream targets of VEGF including VEGF receptors 1-3 and VEGF phosphorylation (Table 1).
Iwaisako (PNAS Vol. 111 pages E3297-E3305 published 2014) teaches that bile duct ligated induced liver fibrosis patients comprise activated hepatic myofibroblasts transdifferentiated from hepatic stella cells (abstract, Figures 1A-1B).
Thus, in view of the combination of Thabut, Wilhelm and Iwaisako, administration of the art-recognized VEGF inhibitor sorafenib is efficacious at treating liver fibrosis in a subject in need where said liver fibrosis contains active hepatic myofibroblasts and said VEGF inhibitor contacts active hepatic myofibroblasts.
The difference between the presently claimed methodology and that of the combination of Thabut, Wilhelm and Iwaisako is that the combination of Thabut, Wilhelm and Iwaisako does not specifically teach contacting hepatic myofibroblasts with a therapeutically effective amount of Formula (I).
Beebe teaches compound of Formula (I) as a potent inhibitor of angiogenesis and growth factors involved in the angiogenic pathway including VEGF and FGF (abstract, page 7301-7302). As shown in Table 1 and Figure 2, Beebe teaches that VEGF-2 are bFGF, are all inhibited in a cell upon contacting said cell with Formula (I), either in-vitro or in-vivo with a dose of 100 mg/kg of Formula(I) (page 7305, pages 7306-7307 Table 1 and Figure 2). Said therapeutically effective amount of Formula (I) administered by Beebe lies inside the therapeutically effective range embraced within [0051] of the instant specification and claim 51. Beebe further teaches that the compound of Formula (I) is more potent at inhibiting VEGF than the hepatic fibrosis treating VEGF inhibitor sorafenib of Thabut, Wilhelm and Iwaisako above (Table 1).
Therefore, one of ordinary skill in the art prior to the time of the invention would have found it prima facie obvious to administer the art-recognized VEGF inhibitor of Formula (I) in order to inhibit VEGF signaling in hepatic myofibroblasts in a subject in view of the combined teachings of Thabut, Wilhelm, Iwaisako and Beebe, arriving at the presently claimed methodology.
MPEP 2143 provides rationale for a conclusion of obviousness including (B): Simple substitution of one known element for another to obtain predictable results;
In the present case, considering that administration of art-recognized VEGF inhibitors are efficacious at treating liver fibrosis that contains activated hepatic myofibroblasts as taught by the combination of Thabut, Wilhelm and Iwaisako, said skilled artisan would have readily predicted that substitution of one VEGF inhibitor for another, such a more potent VEGF inhibitor of Formula (I) of Beebe, in the regimen of Thabut, said VEGF inhibitor would have also effectively inhibited VEGF signaling in the activated hepatic myofibroblasts of the subject with bile-duct ligated induced liver fibrosis, thereby treating said hepatic fibrosis in the afflicted subject.
It is noted that the claimed therapeutic regimen of inhibiting VEGF signaling in a hepatic myofibroblast comprising administering a therapeutically effective amount of Formula (I) has been rendered obvious in view of the combined teachings of Thabut, Wilhelm, Iwaisako and Beebe. Thus, properties that accrue from a process step of contacting a hepatic myofibroblast with the art-recognized VEGF inhibitor, such as inhibiting activation of SMAD2/3 mediated by TGF-beta in the cell (claim 43), or inhibiting VEGFA (claim 45), inhibiting phosphorylation of NFkB (claim 46), or inhibiting the expression of Timp1-Tim3 or Lox11 (claim 47) are all considered characteristic features of the claimed therapeutic regimen.
It is noted that MPEP 2112 discuss the support of rejections wherein the prior art discloses subject matter which there is reason to believe inherently includes functions that are newly cited or is identical to a product instantly claimed. In such a situation the burden is shifted to the applicants to "prove that subject matter shown to be in the prior art does not possess characteristic relied on" (205 USPQ 594, second column, first full paragraph).
In the present case the burden is shifted to Applicant to prove that administered therapeutically effective amount of Formula (I) of Beebe does not inhibit activation of SMAD2/3 mediated by TGF-beta in the cell, nor inhibit VEGFA, nor inhibit phosphorylation of NFkB, nor inhibit the expression of Timp1-Tim3 or Lox11 in the administered cell.
Applicant traverses. Applicant asserts that the combination of references neither teach nor suggest the targeted activated myofibroblast or activated fibroblast cell, the specific signaling pathways, the use of Formula (I) in such cells, the reversing of the activated phenotype or the activity in transdifferentiated fibroblasts. Applicant argues that Thabut studies vascular remodeling and portal hypertension and that sorafenib administration affects vascular tone and does not teach active myofibroblasts or fibroblasts. Applicant further contends that Iwaisako merely identifies the presence of activated myofibroblasts in bile-duct ligation mediated hepatic fibrosis and does not teach administering a compound of Formula (I). Applicant additionally argues that the cited prior art does not specifically teach inhibiting TGF beta, Src or VEGF in an activated myofibroblast cell nor contacting such cells with a therapeutically effective amount of Formula (I).
Applicant further asserts that the examiner has improperly relied on inherency to teach the aforementioned properties are inhibited by the administration of Formula (I) to the bile duct ligated hepatic fibrosis patient comprising an activated myofibroblasts in order to arrive at the presently claimed.
Response to Arguments
Applicant’s arguments, filed 12/09/2025 are acknowledged and have been carefully considered. Regarding Applicant’s contention that the combination of references neither teach nor suggest the targeted activated myofibroblast or activated fibroblast cell, the specific signaling pathways, the use of Formula (I) in such cells, the reversing of the activated phenotype or the activity in transdifferentiated fibroblasts, this argument is unpersuasive. In response to Applicant’s arguments, the Examiner acknowledges and does not dispute Applicants contention that none of the prior art references explicitly teach the administration of the art-recognized Formula (I) to activated myofibroblasts. However, the Examiner recognizes that it must be remembered that the references are relied upon in combination and are not meant to be considered separately as in a vacuum. It is the combination of all of the cited and relied upon references, which make up the state of the art with regard to the claimed invention. The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference and it is not that the claimed invention must be expressly suggested in any one or all of the references; but rather the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. In re Keller, 642 F.2d 413, 208, USPQ 871 (CCPA 1981).
As set forth above, Thabut establishes that administration of overlapping therapeutically effective amounts (1.5 mg/kg) of the art-recognized VEGF inhibitor sorafenib is efficacious at treating bile-duct ligation mediated liver fibrosis in a subject in need. While Thabut is silent as to the capacity of the administered VEGF inhibitor contacting activated myofibroblasts, as evidenced by Iwaisako, said bile-duct ligation mediated liver fibrosis patients contains active hepatic myofibroblasts transdifferentiated from hepatic stella cells (Iwaisako: abstract, Figures 1A-1B). Systemic administration of the art-recognized VEGF inhibitor to the bile-duct ligated hepatic fibrosis patient results in the claimed active step of contacting active hepatic myofibroblasts that are transdifferentiated from any different cell type as required by the claims.
Regarding Applicant’s contention that the combined teachings of Thabut, Wilhelm, Iwaisako and Beebe do not explicitly teach inhibiting specific signaling pathways such as inhibiting TGF beta, Src or VEGF or PDGF signaling in an activated myofibroblast cell, the reversing of the activated phenotype of smooth muscle actin expression, collagen overproduction or the activity in transdifferentiated fibroblasts, this argument is unpersuasive. Such properties are latent properties that will logically flow from the administration of the same therapeutically effective amount of the same art-recognized VEGF inhibitor of Formula (I) to the activated myofibroblast present in the bile-duct ligated hepatic fibrosis patient as taught by the combination of the prior art above. Applicant is reminded of MPEP 2145 wherein the fact that Applicant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious." Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). In the present case, liver stiffness and matrix depositions are effectively treated in bile-duct ligated hepatic fibrosis patients comprising the systemic administration of an art-recognized VEGF inhibitor, a patient population which contains active hepatic myofibroblasts transdifferentiated from hepatic stella cells as taught by Thabut, Wilhelm and Iwaisako above. Considering Beebe teaches that the compound of Formula (I) is more potent at inhibiting VEGF than the hepatic fibrosis treating VEGF inhibitor sorafenib of Thabut, Wilhelm and Iwaisako above, following the preponderance of evidence from the prior art above, the skilled artisan would have readily administered the more potent and art-recognized VEGF inhibitor of Formula (I) to a patient with bile-duct ligated hepatic fibrosis, readily predicting treatment of fibrosis in the afflicted patient. The inhibition of TGF beta, Src or PDGF signaling in an activated myofibroblast cell, the reversing of the activated phenotype of smooth muscle actin expression or collagen overproduction in the administered patient or the activity in transdifferentiated fibroblasts in the hepatic fibrosis patient are all latent properties that would naturally flow from the administration of the same art-recognized VEGF inhibitor of Formula (I) to the same the bile-duct ligated hepatic fibrosis patients comprising active hepatic myofibroblasts transdifferentiated from hepatic stella cells in the same therapeutically effective amount as embodied within the combined prior art above.
Regarding Applicant’s contention that the examiner has improperly relied on inherency of the aforementioned properties of the administered VEGF inhibitor of Formula (I) to the bile duct ligated hepatic fibrosis patient comprising an activated myofibroblast to arrive at the presently claimed rejection, this argument is unavailing. The cited prior art references clearly teach and suggest the administration of an art-recognized VEGF inhibitor, such as Formula (I) of Beebe to treat hepatic fibrosis in a subject in need whom comprises an activated myofibroblast that is transdifferentiated from any cell type. As disclosed above, the inhibition of specific signaling pathways including TGF beta, Src or VEGF or PDGF, inhibition of signaling in an activated myofibroblast cell, the reversing of the activated phenotype of smooth muscle actin expression, collagen overproduction or the activity in transdifferentiated fibroblasts are each latent properties of the systemically administered VEGF inhibitor of Formula (I) to the bile-duct ligated hepatic fibrosis patient whom comprises activated myofibroblasts. This is because apparently identical compositions of matter can not have mutually exclusive properties. See MPEP 2112 wherein "Products of identical chemical composition cannot have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.
As also cited above, the burden has been previously shifted to Applicant to demonstrate with objective evidence that the combination of the cited prior art does not contain these properties, which Applicant has not done. The fact that a characteristic of a composition suggested by the prior art has not been specifically disclosed does not make the product patentable again to Applicant simply because they have determined a property of a composition that flows logically from following the teaching and the suggestions of the prior art that was not previously quantified.
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Conclusion
In view of the rejection set forth above, no claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GEORGE W KOSTURKO whose telephone number is (571)270-5903. The examiner can normally be reached M-F 9:00-5:30.
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/GEORGE W KOSTURKO/Primary Examiner, Art Unit 1621