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 .
Priority
The instant application, filed November 7, 2022, is a national stage entry of PCT/US2021/031277, filed May 7, 2021, which claims priority to U.S. Provisional Application No. 63/022,066, filed May 8, 2020. Receipt was acknowledged of certified copies of papers required by 37 CFR § 1.55.
Information Disclosure Statement
The Information Disclosure Statement filed on 06/02/2026 is acknowledged and found to be in compliance with the provisions of 37 CFR § 1.97. Accordingly, the Information Disclosure Statement has been considered.
Status of Claims
Claims 1-3, 10-17, 19-26, and 44 were subject to a restriction requirement dated 08/28/2025. Following Applicant’s response to the restriction requirement received 10/20/2025, claims 2, 3, 12, 22 and 44 were withdrawn, and claims 1, 10, 11, 13-17, 19-21, and 23-26 were pending and rejected in the Non-final Rejection mailed 03/02/2026. Applicant’s present amendments to the claims were received on 06/02/2026, which are acknowledged and entered.
Claims 2, 3, 10, 13-16, and 44 are cancelled, claims 1, 11, 12, 17, 20, 25, and 26 are amended, and claims 95-97 are added. Claims 19, 21 and 23-24 were maintained as previously presented. As stated above, claims 12 and 22 were previously withdrawn.
Accordingly, claims 1, 11, 17, 19-21, 23-26, and 95-97 are pending and under consideration in the instant application.
Restriction/Election
Applicant’s previous elections without traversing to Group I and species of the invention discussed in the Non-Final Rejection mailed 03/02/2026 at 2-3 were acknowledged. The elections are shown below.
See Group I:
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and the following species of the invention:
The species of vitamin-D receptor (“VDR”) agonist:
A VDR agonist that induces GLP-1 secretion from a target cell as in claim 11.
The species of agent:
Lithocholic acid (“LCA”) - including derivative thereof, as in claim 16.
The restriction and election of species requirements are deemed proper and made FINAL.
Claim Rejections - 35 USC § 112(b) – Withdrawn
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.
Response to Arguments
Applicant’s arguments, see Remarks received 06/02/2026, at 5-6 of 8, with respect to rejections of claims 16, 20, 25, and 26 under 35 USC 112(b) have been fully considered. The rejections of claims 16, 20, 25, and 26 under 35 USC 112(b) have been withdrawn, in view of claim 16 being canceled and the amendments to claims 20, 25, and 26.
The examiner notes that Applicant’s explanation for the cancellation of claim 16 was incomplete. The response abruptly stops in the middle of a sentence. See Remarks received 06/02/2026 at 5 of 8:
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Remarks received 06/02/2026 at 5 of 8.
Claim Rejections - 35 USC § 112 (d) – Necessitated by Amendment
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 17 rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 17 depends on claim 1 and recites “The method of claim 1, wherein the agent is lithocholic acid (LCA), or a pharmaceutically acceptable salt thereof.” The claim indeed fails to further limit the subject matter of the claim upon which it depends. See claim 1, which specifies “wherein the agent is lithocholic acid (LCA), or a pharmaceutically acceptable salt thereof.”.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103 – Maintained / Necessitated by Amendment
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.
Claims 1, 11, 17, 19-21, 23-26, and 95-97 Obvious over WO’961 in view of Ferrell 2019 and Chatterjee 2005
The previous rejections of claims 1, 10, 11, 13-17, 19-21, and 23-26 under 35 U.S.C. 103 as being unpatentable over WO’961 in view of Ferrell 2019 and Chatterjee 2005, are effectively maintained.1 Amendments to the claims and the addition of claims 95-97 are discussed in the Reiterated Rejections section following Response to Arguments.
Response to Arguments
Applicant’s arguments, see Remarks received 06/02/2026, at 6-8 of 8, with respect to rejections of claims 1, 10, 11, 13-17, 19-21, and 23-26 under 35 USC 103 have been fully considered but they are not persuasive.
First, Applicant does not contest currently the rejections of the dependent claims. See Remarks received 06/02/2026, at 7 of 8:
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Remarks received 06/02/2026, at 7 of 8
Instead, Applicant’s position is that the references WO’961, Ferrell 2019 and Chatterjee 2005 teach away from administering LCA “at least because each reference teaches that LCA is toxic”, and as a result, “one of skill would not be motivated to choose to administer LCA to a subject”. See Remarks received 06/02/2026, at 7 of 8. Applicant’s position is not persuasive because 1) it begins on an improper foundation possibly due to an incomplete reading of WO’961, and 2) disregards the ordinary practitioner’s ability to balance the toxicity of an active pharmaceutical ingredient (an “API”) with its therapeutic benefit.
First, Applicant begins stating that “WO '961 describes applying LCA, and other molecules, to hepatic cells in culture (see Example 2), but it does not teach or suggest administering LCA to a subject.” See Remarks received 06/02/2026, at 7 of 8.
Applicant’s foundation is improper because WO’961 explicitly teaches a method of treating fibrosis in a subject, comprising administering a therapeutically effective amount of LCA. WO’961 at 93, claim 1, teaches “A method of treating fibrosis in a subject, comprising: administering a therapeutically effective amount of a vitamin D receptor agonist to a subject having a fibrosis, thereby treating the fibrosis.”
WO’961 states at 92, that “the scope of the invention is defined by the following claims.”
WO’961 explicitly defines LCA as a vitamin D receptor agonist. See WO’961 at 16-17, section titled “Vitamin D agonist or analog”, which states that it includes “Any compound, synthetic or natural, that binds to and activates the vitamin D receptor” and expressly includes “bile acid derivatives such as lithochoic acid [sic] (LCA)….” The indicated spelling here “lithochoic” is a typographical error. See, e.g., WO’961 at 33 (“lithocholic acid [LCA]”) (brackets in original); id. at 8-9 (“
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…
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”).
Therefore, WO’961 at 93, claim 1, explicitly teaches a method of treating fibrosis in a subject, comprising: administering a therapeutically effective amount of LCA to a subject having a fibrosis, thereby treating the fibrosis. Accordingly, Applicant’s position begins on a foundation that is improper possibly due to an incomplete reading of WO’961.
As explained in the Non-Final Rejection mailed 03/02/2026 at 13-18, treating fibrosis is consistent with treating diabetes (by treating or reducing the risk of fibrosis). Vitamin D receptor agonists suppress pro-inflammatory and pro-fibrotic gene expression and signalling. Several of the sections explaining the mechanism were cited in the Non-Final Rejection. WO’961 provides a figure that helps summarize the path. See WO’961 at 5, discussion of FIG. 13 that exemplifies vitamin D as the vitamin D receptor agonist, and the respective figure (appearing at pdf page 111 of 114):
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WO’961 at 5.
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WO’961 at FIG. 13.
Second, regarding the teaching away and toxicity concerns. At no point in Applicant’s position does Applicant recognize the ordinary practitioner’s ability to balance the toxicity of an API with its therapeutic benefit.
The inventors of WO’961 at 32-33 expressly acknowledged that bile acids were toxic. The inventors themselves cite Chatterjee 2005 on page 23. The very first page of Chatterjee 2005 indeed states that LCA is “highly toxic”. But the inventors of WO’961 do not teach or suggest that one of skill in the art administer a highly toxic amount of LCA to a subject. Instead, they explicitly teach administering “a therapeutically effective amount” of LCA. See claim 1 of WO’961. They further exemplify administering LCA in vitro as a proof of concept, wherein its administration caused translocation of the vitamin D receptor into the nucleus. See WO’961 at 55, and associated figures.
Further, the inventors of WO’961 expressly acknowledged that the therapeutic activation by LCA of vitamin D receptors occurs in vivo. See WO’961 at 33 (“In the intestine, bacteria deconjugate and dehydroxylate bile acids to form the more toxic secondary bile acids (lithocholic acid [LCA] and deoxycholic acid [DCA]), after which they are absorbed actively from the small intestine, with each molecule undergoing multiple enterohepatic circulations back to the liver before being excreted.”) (brackets in the original).
They continue to explain that the body has ample means of detoxifying excess LCA. See WO’961 at 33 (“Bile acids are potentially hepatotoxic and are tightly controlled to prevent accumulation of concentrations that would result in liver injury and subsequent fibrosis. Three NHRs, vitamin D receptor (VDR), farnesoid X receptor (FXR) and PXR are capable of binding bile acids, heterodimerizing with RXR and then transactivating a spectrum of target genes that controls both the levels and detoxification of bile acids. FXR is the primary bile acid receptor that controls the rate of cholesterol breakdown and bile acid flux in the liver, while PXR, as mentioned above, controls the detoxification of bile acids….”).
The section of Ferrell 2019 that Applicant cites in Remarks received 06/02/2026, at 7 of 8, “Ferrell, page 260 second column”, as teaching away from LCA administration, further confirms that this process of therapeutic activation by LCA of vitamin D receptors occurs in vivo. See Ferrell 2019 at 260 (“LCA is a toxic and highly insoluble bile acid, most of which is excreted into feces, though small amounts of LCA (approximately 2%) are circulated to the liver and sulfoconjugated for secretion into urine.”).
Finally, it was quite clear that the therapeutically effective amount of LCA required to activate VDR and initiate the protective benefits of VDR agonism fell below the highly toxic amount needed to induce hepatoxicity. WO’961 at 33 explained that the nuclear hormone receptor PXR “controls the detoxification of bile acids”. Now see Chatterjee 2005 at 188 (“…the functional LCA concentration for PXR activation is about 10-fold higher than that needed to activate VDR (Makishima et al., 2002).”). Thus, it was known that about 10-fold less LCA was needed to activate VDR prior to PXR having to activate and detoxify the excess LCA.
Therefore, there is simply no evidence to suggest that the inventors of WO’961 disregarded the utility of LCA as an active to administer in their methods due to an inability to reconcile its toxicity with its therapeutic benefit. One of ordinary skill in the art at the time of filing, reading WO’961 in view of Ferrell 2019 and Chatterjee 2005, would not be dissuaded from taking advantage of a naturally occurring treatment axis. Instead, that ordinary person would find a reasonable expectation of success in exploiting it by administering a therapeutically effective amount of LCA.
As a result, Applicant’s position that the known toxicity of LCA would teach away from administering LCA 1) begins on a foundation that is improper possibly due to an incomplete reading of WO’961, and 2) disregards the ordinary practitioner’s ability to balance the toxicity of an API with its therapeutic benefit.
Therefore, Applicant’s position is not persuasive.
Reiterated Rejection:
Claims 1, 11, 17, 19-21, 23-26, and 95-97 are Obvious over WO’961 in view Ferrell 2019 and Chatterjee 2005
Claims 1, 11, 17, 19-21, 23-26, and 95-97 are rejected under 35 U.S.C. 103 as being unpatentable over WO’961 in view of Ferrell 2019 and Chatterjee 2005.2
Instant claim 1 recites:
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Instant claim 1.
However, WO’961 teaches 1) a method of treating diabetes in a subject (by treating or reducing the risk of fibrosis) comprising administering a VDR agonist, 2) discloses that LCA is a VDR agonist, and 3) that LCA induces expression of a sulfotransferase (SULT2A1).
WO’961
WO’961 at 93, claim 1, teaches “A method of treating fibrosis in a subject, comprising: administering a therapeutically effective amount of a vitamin D receptor agonist to a subject having a fibrosis, thereby treating the fibrosis.” (emphases added).
WO’961 states at 92, that “the scope of the invention is defined by the following claims.”
WO’961 explicitly defines LCA as a vitamin D receptor agonist. See WO’961 at 16-17, section titled “Vitamin D agonist or analog”, which states that it includes “Any compound, synthetic or natural, that binds to and activates the vitamin D receptor” and expressly includes “bile acid derivatives such as lithochoic acid [sic] (LCA)….” The indicated spelling here “lithochoic” is a typographical error. See, e.g., WO’961 at 33 (“lithocholic acid [LCA]”) (brackets in original); id. at 8-9 (“
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Vitamin D receptor agonists suppress pro-inflammatory and pro-fibrotic gene expression and signalling. WO’961 provides a figure that helps summarize the path. See WO’961 at 5, discussion of FIG. 13 that exemplifies vitamin D as the vitamin D receptor agonist, and the respective FIG. 13 (appearing at pdf page 111 of 114):
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WO’961 at 5.
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WO’961 at FIG. 13.
While the inventors of WO’961 at 32-33 acknowledge that bile acids like LCA are toxic, they:
Explain that the therapeutic activation by LCA of vitamin D receptors occurs in vivo, see WO’961 at 33:
In the intestine, bacteria deconjugate and dehydroxylate bile acids to form the more toxic secondary bile acids (lithocholic acid [LCA] and deoxycholic acid [DCA]), after which they are absorbed actively from the small intestine, with each molecule undergoing multiple enterohepatic circulations back to the liver before being excreted.”) (brackets in the original).
WO’961 at 33.
Explain that the body has ample means to detoxify excess LCA, see WO’961 at 33:
Bile acids are potentially hepatotoxic and are tightly controlled to prevent accumulation of concentrations that would result in liver injury and subsequent fibrosis. Three NHRs, vitamin D receptor (VDR), farnesoid X receptor (FXR) and PXR are capable of binding bile acids, heterodimerizing with RXR and then transactivating a spectrum of target genes that controls both the levels and detoxification of bile acids. FXR is the primary bile acid receptor that controls the rate of cholesterol breakdown and bile acid flux in the liver, while PXR, as mentioned above, controls the detoxification of bile acids….
WO’961 at 33.
Exemplify administering LCA in vitro as a proof of concept, wherein its administration caused translocation of the vitamin D receptor into the nucleus. See WO’961 at 55, and associated figures.
Indeed, WO’961 exemplifies methods of treating fibrosis in a subject comprising administering vitamin D receptor agonists.
Described herein are methods of treating fibrosis that are based on the unexpected discovery that a specialized subset of cells within the liver responds to compounds that bind to or activate the vitamin D receptor (VDR, NRlIl) to influence the processes of liver injury, inflammation and fibrogenesis. Cells that express and respond to the VDR in liver include, but are not limited to hepatic stellate cells (HSCs), myofibroblasts, Kupffer cells (KCs), and sinusoidal endothelial cells (SECs). These cells types are frequently referred to as hepatic non-parenchymal cells (NPCs). In addition, there are similar specialized cells within the pancreas and kidney that respond in a similar manner, including but not limited to pancreatic stellate cells and renal mesangial cells.
Thus, one embodiment of the disclosure is a method of treating fibrosis in a subject. The method can include administering a therapeutically effective amount of vitamin D receptor agonist (such as lα,25 dihydroxyvitamin D3, (1,25-(OH)2- D3) or a precursor thereof, a vitamin D analog, a vitamin D receptor ligand, or a vitamin D receptor agonist precursor), to a subject having a fibrosis or at risk for developing fibrosis, thereby treating the fibrosis.
WO’961 at 2-3 (emphases added).
WO’961 explains that diabetes contributes to the high prevalence of end stage renal disease (“ESRD”), and that ESRD is characterized by significant renal fibrosis:
Almost all forms of end stage renal disease (ESRD) are characterized by significant renal fibrosis. A number of cardiovascular diseases, the aging population, and diabetes contribute to the high prevalence of ESRD. Two-thirds of ESRD patients are treated by frequent (2-3 times weekly) and long dialysis sessions and one-third is treated by kidney transplantation. In Europe, kidney replacement therapy is consuming 2% if the healthcare budget for only 0.1% of the population being treated.
WO’961 at 2 (emphasis added).
WO’961 further explains that hepatic fibrosis and pancreatic fibrosis are driven by inflammatory changes:3
Hepatic fibrosis, the accumulation of abnormal extracellular matrix (ECM) proteins and a resultant loss of liver function, is an accompaniment of an inflammation-driven wound healing process triggered by chronic liver injury. The main causes of liver injury leading to fibrosis in Western societies include chronic hepatitis C virus (HCV) infection, alcohol abuse, chronic hepatitis B (HBV) infection, iron overload as occurs in hereditary hemochromatosis, and increasingly, non-alcoholic steatohepatitis (NASH). The inflammatory process ensuing from hepatic injury triggers a variety of cellular responses including cell repair, hepatocyte regeneration, increased extracellular matrix turnover, and ultimately in some patients significant fibrosis. Progressive fibrosis of the liver eventually can result in cirrhosis, portal hypertension and hepatocelluar carcinoma.
WO’961 at 1, and
Fibrosis of the pancreas is caused by such processes as necrosis/apoptosis, inflammation, and duct obstruction. The initial event that induces fibrogenesis in the pancreas is an injury that may involve the interstitial mesenchymal cells, the duct cells and/or the acinar cells. Damage to any one of these tissue compartments of the pancreas is associated with cytokine-triggered transformation of resident fibroblasts/pancreatic stellate cells into myofibroblasts and the subsequent production and deposition of extracellular matrix. Depending on the site of injury in the pancreas and the involved tissue compartment, predominantly inter(peri)lobular fibrosis (as in alcoholic chronic pancreatitis), periductal fibrosis (as in hereditary pancreatitis), periductal and interlobular fibrosis (as in autoimmune pancreatitis) or diffuse inter- and intralobular fibrosis (as in obstructive chronic pancreatitis) develops. Given the foregoing, it would be desirable to have methods of treating, preventing, and ameliorating fibrosis, such as fibrosis of the liver, kidney, or pancreas.
WO’961 at 2.
WO’961 explains that treatment of hepatic non-parenchymal cells (“NPCs”)4 with VDR agonists slows, prevents, or reverses inflammatory and fibrotic changes to the liver:
Treatment of hepatic NPCs with VDR agonists has profound effects on gene expression in NPCs. For example, when HSCs are cultured on plastic, they undergo a process called "activation," wherein they change phenotype from a retinol- and lipid-rich cell into an extracellular matrix-producing cell that is ultimately responsible for the production of scarring within the liver (fibrogenesis). VDR ligands prevent or retard this activation process, and reverse the process in some embodiments. Moreover, treatment of HSCs with VDR ligands markedly attenuates pro-inflammatory and pro-fibrotic gene expression induced by treating HSCs with either bacterial lipopolysaccharide endotoxin (LPS) or transforming growth factor beta 1 (TGF-βl). In particular, VDR ligands attenuate or abrogate LPS-induced pro-inflammatory chemokine production and TGF-β-induced pro- fibrotic collagen production by HSCs (Table 1). LPS is a potent activator of the innate immune system while TGF-β is a family of three proteins that regulate differentiation, proliferation and many other functions in a wide range of cell types. Thus, VDR ligands and other VDR agonists play a therapeutic role in the prevention of liver injury, inflammation, and fibrogenesis in persons with liver diseases, including but not limited to chronic viral hepatitis (Hepatitis B and Hepatitis C infection), alcohol-induced liver disease, non-alcoholic steatohepatitis, autoimmune liver diseases, and genetic liver diseases, such as hereditary hemochromatosis, alpharantitrysin deficiency and Wilson's disease.
WO’961 at 20.
WO’961 teaches that 1) VDR is highly expressed in NPCs, 2) lithocholic acid (“LCA”) activates VDR, and 3) LCA induces SULT2A1 expression:
Despite its relatively high expression level in NPCs, the role of VDR in these cells was unknown prior to this disclosure. VDR possesses the common nuclear receptor structure, for instance is comprised of an N-terminal activation domain, a DNA-binding region (DBD) with two zinc finger domains, a hinge region and a ligand-binding domain (LBD). VDR activated gene transcription requires initial nuclear translocation via importin-α, heterodimerization with RXR, (Yasmin et al, 2005. J Biol Chem., 280(48):40152-60), and binding to response elements present in target genes. VDR regulates genes associated with the maintenance of calcium and phosphate homeostasis in the intestine and kidney. The signal initiated by VDR/RXR heterodimers is modulated by the association of co-activating or co-repressing proteins and also depends on other signaling partners in the nuclear compartment (Ebert et ah, 2006. MoI Cell Endocrinol., 248(1-2): 149-59). The VDR/RXR heterodimer is non-permissive, in that the presence or absence of RXR ligands does not affect VDR responses (Shulman et ah, 2004. Cell, 116(3):417-29). Until recently, the only known physiological ligand for VDR was calcitriol. However, specific bile acids such as LCA and some derivatives (LCA-acetate, LC A- formate, 3-keto LCA) may activate VDR. These bile acid VDR agonists have been shown to induce SULT2A1 expression, a sulfo-conjugating phase II enzyme in intestinal mucosa, which may provide a key defense response of the intestine against the toxic and carcinogenic effects of bile acids (Chatterjee et al., 2005. Methods Enzymol., 400: 165-91).
WO’961 at 22-23 (emphases added).
WO’961 explains that the therapeutic benefit of VDR agonism in the liver was overlooked because hepatocytes usually exhibit very low levels of VDR:
It was previously thought that the liver lacked VDR expression because hepatocytes, the most abundant cell population in liver, usually exhibit very low levels of the receptor: the total level of VDR in rat liver is 1, 300-fold lower than in intestine. It is possible that the increase in intracellular Ca2+ levels observed in rat hepatocytes in response to 1,25-(OH)2-D3 may be due to an unrelated membrane receptor or an indirect mechanism rather than VDR-mediated signaling (Mailhot et ah, 2000. Endocrinology., 141 :891-900). However, 1,25-(OH)2-D3 has a significant effect on liver cell physiology during the compensatory growth process following the partial hepatectomy in the rat (Segura et ah, 1999. Histochem Cell Biol., 112(2): 163-7; Gascon-Barre et α/., 1994. J Clin Invest, 93(5):2159-67). Thus, VDR expression was examined in freshly isolated hepatic NPC populations. Surprisingly, it was shown herein that VDR is abundantly expressed in HSCs, KCs and SECs isolated from normal rat livers and the VDR in these cells is fully functional as determined by the VDR-dependent induction of CYP24A1 expression by lα,25-(OH)2-D3.
WO’961 at 23 (emphases added).
Therefore, WO’961 discloses 1) a method of treating diabetes in a subject (by treating or reducing the risk of fibrosis) comprising administering a VDR agonist, 2) discloses that LCA is a VDR agonist, and 3) that LCA induces expression of a sulfotransferase (SULT2A1).
While WO’961 teaches every limitation of claim 1, the following references provide motivation to adapt the method of treating diabetes (by treating or reducing the risk of fibrosis) disclosed in WO’961 to more generally expand upon the known therapeutic benefits that VDR agonism provides for diabetic subjects.
For example,
Ferrell 2019 explains that LCA is known to be a potent endogenous TGR5 agonist, and that the activation of TGR5 stimulates the release of GLP-1 from enteroendocrine L-cells to stimulate insulin secretion from β-cells and increase insulin sensitivity.
Chatterjee 2005 explains that LCA is known to activate VDR, which in turn causes the activation of SULT2A to detoxify LCA.
Ferrell 2019
Ferrell 2019 at 261 discloses that the Takeda G protein-coupled receptor 5 (“TGR5”) is agonized by LCA, and that TGR5 activation simulates release of GLP-1.
In the liver, TGR5 is expressed in sinusoidal endothelial cells, Kupffer cells (hepatic resident macrophages), stellate cells, and biliary epithelial cells in bile ducts, but not in hepatocytes [39-41], and the secondary bile acids LCA and DCA are potent en-dogenous TGR5 agonists (LCA>DCA>CDCA>CA). TGR5 is expressed in the epithelium of human gallbladder and con-trols gallbladder refiling [42]. TGR5 also plays a key role in bile acid metabolism and fasting-induced hepatic steatosis [43]. In the colon, TGR5 mediates bile acid-induced gastrointestinal motility, transit time and defecation [44]. In the intestine and macrophage, activation of TGR5 protects against inflamma-tion [45]. TGR5 also plays a critical role in the control of glu-cose homeostasis [46]. Activation of TGR5 stimulates the re-lease of glucagon-like peptide-1 (GLP-1) from enteroendo-crine L-cells to stimulate insulin secretion from β-cells and in-crease insulin sensitivity. In adipose tissue, activation of TGR5 induces thyroid hormone deiodinase type 2 (DIO2), which converts thyroid hormone thyroxine (T4) to triiodothyronine (T3) to stimulate energy metabolism and white adipose tissue browning (Fig. 2). CDCA increases brown adipose tissue in humans, likely through TGR5-mediated increase of uncou-pling protein and DIO2 expression [47]. TGR5 knockout mice are protected from cholesterol gallstone disease and high fat diet (HFD) induced obesity [48,49]. FXR and TGR5 are co-ex-pressed in L-cells, and activation of intestinal FXR stimulates TGR5 gene transcription via an FXR response element located in the TGR5 gene promoter; this crosstalk stimulates GLP-1 secretion [50]. It is therefore likely that some of the reported FXR effects on glucose metabolism may be due to TGR5 sig-naling in the gut.
Ferrell 2019 at 261 (emphases added).
Chatterjee 2005
Chatterjee 2005 explains that endogenous SULT2A1 mRNA and protein expression is induced by vitamin D:
Endogenous SULT2A1 mRNA and protein expression is induced by vitamin D (Echchgadda et al., 2004a). Figure 2 shows an example of this induction in liver cells and in the mouse liver. Treatment of HepG2 hepatoma cells with vitamin D (1α,25‐dihydroxy vitamin D3) for 24 h induced SULT2A1 mRNAs ∼6‐fold in a RT‐PCR assay (Fig. 2A); in mice injected with vitamin D, Sult2A1 mRNAs in the liver increased ∼3‐fold in a Northern blot assay (Fig. 2B). This induction reflected activation of the corresponding promoter (Fig. 3). In Caco‐2 intestinal cells, vitamin D induced the human promoter (from −1102 to 10) ∼6‐fold and the mouse promoter (from −292 to 42) ∼4.5‐fold; similar induction of the promoter has been observed in HepG2 hepatoma cells. Vitamin D induction of the human CYP3A4 promoter (from the CYP3A‐Luc construct) is also shown (Fig. 3A). This construct contains a proximal (at −173) and a distal (at −7715) VDR‐binding element (Drocourt 2002, Makishima 2002) in the CYP3A4 promoter.
Chatterjee 2005 at 174-175.
Figure 2 of Chatterjee 2005 is reproduced below:
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Chatterjee 2005 at 174, Figure 2.
Chatterjee 2005 explains that LCA and its derivatives agonize VDR and induce SULT2A1:
Secondary bile acid lithocholic acid (LCA) and its derivatives (LCA‐acetate, LCA‐formate, 3‐keto LCA) are known to serve as sensitive VDR agonists and to induce VDR target genes (Adachi 2005, Makishima 2002). Figure 3B shows induction of the SULT2A1 promoter by LCA‐acetate. The LCA‐mediated induction of SULT2A1 may be a key defense response of the intestinal and hepatobiliary tissues against the toxic/carcinogenic effects of bile acids.
Chatterjee 2005 at 175.
Chatterjee 2005 explains that the LCA-mediated induction of SULT2A1 may have emerged to protect from the toxicity of disrupted bile acid/sterol homeostasis caused by endogenous or exogenous factors:
LCA and LCA derivatives are agonist ligands of VDR and are able to induce CYP2, CYP3, and several other VDR target genes at micro molar concentrations (Adachi et al., 2005). The SULT2A1 promoter is also induced by LCA‐acetate (Fig. 3B). We predict that VDR takes a central role in LCA‐mediated induction of the SULT2A1 gene, even though PXR and FXR, the two NRs that are also activated by LCA, can induce SULT2A1 (Song et al., 2001; Sonoda et al., 2002). This prediction is made on the ground that LCA is an FXR antagonist (Yu et al., 2002) and that the functional LCA concentration for PXR activation is about 10‐fold higher than that needed to activate VDR (Makishima et al., 2002). In conclusion, a role for the VDR pathway in the basal and induced expression of SULT2A1, a phase II transferase, may have emerged to protect cells of the first‐pass tissues from the adverse effects of disrupted bile acid/sterol homeostasis caused by endogenous or exogenous factors.
Chatterjee 2005 at 187-188 (emphases added).
Claim 1 was Obvious at the Time of Filing
One having ordinary skill in the art at the time of filing would have a reasonable expectation of success in developing a method of treating diabetes in a subject in need thereof comprising administering an agent that increases the levels of a sulfotransferase in the subject, wherein the agent is LCA, because WO’961 discloses that 1) fibrosis, a common complication of diabetes, may be treated by administering a VDR agonist, 2) LCA is a VDR agonist, and 3) LCA induces the expression of SULT2A1, a sulfotransferase. One having ordinary skill in the art would be further motivated to develop a method of treating diabetes comprising administering LCA because:
Ferrell 2019 explains that LCA is known to be a potent endogenous TGR5 agonist, and that TGR5 activation stimulates the release of GLP-1 from enteroendocrine L-cells to stimulate insulin secretion from β-cells and increase insulin sensitivity, and
Chatterjee 2005 explains that LCA and its derivatives serve as sensitive VDR agonists, and that the LCA-mediated induction of SULT2A1 may protect cells of the first‐pass tissues from the adverse effects of disrupted bile acid/sterol homeostasis caused by endogenous or exogenous factors.
The person of ordinary skill art at the time of filing would have a reasonable expectation of success in balancing any concerns regarding the known toxicity of LCA by administering to the diabetic subject a therapeutically effective amount of LCA as taught by WO’961, and not a toxic amount. It would take only ordinary and routine experimentation to determine safe and effective amounts, because as WO’961 at 33 explains, “PXR … controls the detoxification of bile acids…”, and Chatterjee 2005 at 188 explains that “the functional LCA concentration for PXR activation is about 10‐fold higher than that needed to activate VDR”. Therefore, it was known that about 10-fold less LCA was needed to activate VDR prior to PXR having to activate and detoxify the excess LCA.
Accordingly, claim 1 was obvious at the time of filing.
Claim 11 was Obvious at the Time of Filing
Claim 11 recites:
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Instant claim 11.
WO’961, Ferrell 2019, and Chatterjee 2005 are relied upon as above.
Ferrell 2019 explains that LCA is a potent TGR5 agonist and that TGR5 activation simulates GLP-1 release from enteroendocrine L-cells.
Therefore, claim 11 was obvious for the reasons given above, and for the same reasons claim 1 was obvious at the time of filing.
Claim 17 was Obvious at the Time of Filing
Claim 17 recites:
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Instant claim 17.
WO’961, Ferrell 2019, and Chatterjee 2005 are relied upon as above.
Claim 17 fails to further limit claim 1 and recites administration of the same agent. Therefore, it was obvious for the same reasons claim 1 was obvious at the time of filing.
Claim 19 was Obvious at the Time of Filing
Claim 19 recites:
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Instant claim 19.
WO’961, Ferrell 2019, and Chatterjee 2005 are relied upon as above.
WO’961 discloses pharmaceutical compositions of the VDR agonists. See, e.g., WO’961 at 37:
The present disclosure includes a treatment for fibrosis, for instance hepatic, renal or pancreatic fibrosis, in a subject. The method includes administering vitamin D receptor agonists, such as lα,25(OH)2 D3, vitamin D precursors (for instance, 25-hydroxy-D3 (25-OH-D3) (calcidiol); vitamin D3 (cholecalciferol); or vitamin D2 (ergocalciferol)), vitamin D analogs, and vitamin D receptor agonists precursors to the subject in a pharmaceutically acceptable carrier and in an amount effective to inhibit (for example to relieve, cure, ameliorate, or prevent) the development, progression, or manifestation of fibrosis in the subject. The present disclosure also contemplates the administration of a therapeutic composition comprising more than one VDR agonist, as well as VDR agonists in combination with other therapies.
The vehicle in which the VDR agonist is delivered can include pharmaceutically acceptable compositions of the compounds, using methods well known to those with skill in the art. Any of the common carriers, such as sterile saline or glucose solution, can be utilized. The vehicle also can contain conventional pharmaceutical adjunct materials such as, for example, pharmaceutically acceptable salts to adjust the osmotic pressure, lipid carriers such as cyclodextrins, proteins such as serum albumin, hydrophilic agents such as methyl cellulose, detergents, buffers, preservatives and the like. A more complete explanation of parenteral pharmaceutical carriers can be found in Remington: The Science and Practice of Pharmacy (19th Edition, 1995) in chapter 95.
Embodiments of other pharmaceutical compositions can be prepared with conventional pharmaceutically acceptable carriers, adjuvants, and counter-ions, as would be known to those of skill in the art. The compositions in some embodiments are in the form of a unit dose in solid, semi-solid, and liquid dosage forms, such as tablets, pills, capsules, lozenges, powders, liquid solutions, or suspensions.
In some embodiments, sustained release of the pharmaceutical preparation that includes an effective amount of a VDR agonist is beneficial. Slow-release formulations are known to those of ordinary skill in the art. By way of example, sustained-release tablets can be formulated so that the active ingredient is embedded in a matrix of insoluble substance so that the dissolving drug emerges gradually through the holes in the matrix. In some formulations, the matrix physically swells to form a gel, so that the drug has first to dissolve in matrix, then exit through the outer surface.
WO’961 at 37-38.
One having ordinary skill in the art at the time of filing would have a reasonable expectation of success in formulating the agent (i.e., the VDR agonist LCA) with a pharmaceutical composition because WO’961 explains that the VDR agonist may be administered in pharmaceutical compositions.
Therefore, claim 19 was obvious for the reasons given above, and for the same reasons claim 1 was obvious at the time of filing.
Claim 20 was Obvious at the Time of Filing
Claim 20 recites:
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Instant claim 20.
WO’961, Ferrell 2019, and Chatterjee 2005 are relied upon as above.
WO’961 explains that the VDR agonist, which may be formulated with a pharmaceutical composition as explained above in claim 19, may be delivered rectally or to target tissue:
It is not intended that the present disclosure be limited to a particular mode of administration. A variety of modes of administration are contemplated, including intravenously, intramuscularly, subcutaneously, intradermally, intraperitoneally, intrapleurally, intrathecally, orally, rectally, transdermally, by inhalation, and topically. In certain embodiments, the therapeutic compositions are administered via suppository, or in tablet or capsule formulations for oral delivery. In one embodiment, administration of the therapeutic compositions occurs at night. In another embodiment, multiple doses (e.g., 3 or 4) are provided in a 24 hour period. In a further embodiment, the administration of the therapeutic composition is by pulse intravenous therapy. In one example, the therapeutic compositions are administered via a transdermal patch (skin patch).
For instance a VDR agonist is administered, in one embodiment, intravenously in any conventional medium for intravenous injection, such as an aqueous saline medium, or in blood plasma medium. In other embodiments, administration is oral, for instance as a liquid or a pill. In other embodiments, administration is rectal, for example via a suppository containing the VDR agonist. In still other embodiments, administration is by direct infusion into a hepatic, renal, or pancreatic artery with a pharmaceutical composition that contains a vitamin D receptor agonist. In yet other embodiments, a target delivery technology is used to deliver the composition to the target tissue, for instance the liver, the kidney, or the pancreas. In one specific, non-limiting example, the vitamin D receptor agonist is designed to be taken up by the target tissue, or is linked to a target-specific carrier molecule that facilitates uptake by the target cells. For instance, for hepatic stellate cells, the vitamin D receptor agonist is conjugated to a receptor for low- and/or high-density lipoproteins (LDL and/or HDL receptors).
WO’961 at 40.
One having ordinary skill in the art at the time of filing would have a reasonable expectation of success in formulating the agent (i.e., the VDR agonist LCA) with a pharmaceutical composition because WO’961 explains that the VDR agonist may be administered in pharmaceutical compositions. One having ordinary skill in the art at the time of filing would have a reasonable expectation of success in formulating the pharmaceutical composition to restrict delivery of LCA to the gastrointestinal tract of the subject because WO’961 teaches rectal administration of the VDR agonist, for example, through a suppository.
Therefore, claim 20 was obvious for the reasons given above, and for the same reasons claims 19 and 1 were obvious at the time of filing.
Claim 21 was Obvious at the Time of Filing
Claim 21 recites
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Instant claim 21.
WO’961, Ferrell 2019, and Chatterjee 2005 are relied upon as above
The rejection set forth above is pertinent to all types of diabetes. As the Instant Specification explains, inflammatory diseases are common complications of diabetes:
Serious long-term complications (i.e. chronic side effects) include cardiovascular disease (doubled risk), inflammatory diseases, chronic renal failure, retinal damage (which can lead to blindness), nerve damage (of several kinds), and microvascular damage, which may cause impotence and poor wound healing.
Instant Specification at 20, paragraph[0071] (emphasis added).
WO’961 explains that hepatic fibrosis and pancreatic fibrosis are driven by inflammatory changes. See supra discussion of WO’961.
Accordingly, claim 21 was obvious for the reasons given above, and for the same reasons claim 1 was obvious at the time of filing.
Claim 23 was Obvious at the Time of Filing
Claim 23 recites :
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Instant claim 23.
WO’961, Ferrell 2019, and Chatterjee 2005 are relied upon as above
As set forth in the rejection for claim 1, Ferrell 2019 explains that LCA is known to be a potent endogenous TGR5 agonist, and that TGR5 activation stimulates the release of GLP-1 from enteroendocrine L-cells to stimulate insulin secretion from β-cells and increase insulin sensitivity.
The Instant Specification explains that “GLP-1 has the ability to decrease blood glucose levels in a glucose-dependent manner by enhancing insulin secretion from the pancreas.” Instant Specification at 58, paragraph [00213].
One having ordinary skill in the art at the time of filing would have a reasonable expectation of success in developing the method of claim 1, wherein the administering reduces glucose levels in the serum of a subject, because 1) Ferrell 2019 explains that LCA is a TGR5 agonist, and that TGR5 activation stimulates the release of GLP-1, and 2) the Instant Specification explains that GLP-1 decreases blood glucose in a glucose-dependent manner.
Therefore, claim 23 was obvious for the reasons given above, and for the same reasons claim 1 was obvious at the time of filing.
Claims 24 and 25 were Obvious at the Time of Filing
Claims 24-25 recite:
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Instant claims 24-25.
WO’961, Ferrell 2019, and Chatterjee 2005 are relied upon as above
WO’961 explains that subjects of disclosed methods include both human and non-human mammals:
Subject: Living multi-cellular vertebrate organisms, a category that includes both human and non-human mammals. The methods and compositions disclosed herein have equal applications in medical and veterinary settings. Therefore, the general term "subject" is understood to include all animals, including, but not limited to, humans or veterinary subjects, such as other primates, dogs, cats, horses, and cows.
WO’961 at 15-16.
One having ordinary skill in the art at the time of filing would have a reasonable expectation of success in developing the method of claim 1, wherein the subject is a mammal, because WO’961 explains that subjects of the disclosed methods include all animals. One having ordinary skill in the art at the time of filing would have a reasonable expectation of success in developing the method of claim 1, wherein the subject is a human, because WO’961 explains that subjects of the disclosed methods include humans.
Therefore, claims 24 and 25 were obvious for the reasons given above, and for the same reasons claim 1 was obvious at the time of filing.
Claim 26 was Obvious at the Time of Filing
Claim 26 recites:
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Instant claim 26.
WO’961, Ferrell 2019, and Chatterjee 2005 are relied upon as above
WO’961 explains that hepatocytes show VDR expression:
It was previously thought that the liver lacked VDR expression because hepatocytes, the most abundant cell population in liver, usually exhibit very low levels of the receptor: the total level of VDR in rat liver is 1, 300-fold lower than in intestine.
WO’961 at 23 (emphases added).
Further, Ferrell 2019 explains that LCA is known to be a potent endogenous TGR5 agonist, and that TGR5 activation stimulates the release of GLP-1 from enteroendocrine L-cells to stimulate insulin secretion from β-cells and increase insulin sensitivity. See supra discussion of Ferrell 2019.
One having ordinary skill in the at the time of filing would have a reasonable expectation of success in developing the method of claim 1, wherein the target cell is a hepatocyte, enteroendocrine cell, an epithelial cell, an L-cell, or a neuron, because WO’961 and Ferrell 2019 explain that LCA induces activity in hepatocytes and in enteroendocrine L-cells, respectively.
Therefore, claim 26 was obvious for the reasons given above, and for the same reasons claim 1 was obvious at the time of filing.
Claim 95 was Obvious at the Time of Filing
Claim 95 recites:
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Instant claim 95.
WO’961, Ferrell 2019, and Chatterjee 2005 are relied upon as above.
As evident from the text of the claim, claim 95 sets forth a multivariate calculation with undefined variables. The claim 1) fails to specify “an appropriate control”, and 2) does not identify a specific “activity of sulfotransferase” that “is increased by at least 50%…”.
However, one having ordinary skill in the art at the time of filing would have a reasonable expectation of success in increasing “the activity of sulfotransferase … by at least 50%” as compared to some “appropriate control” by administering LCA because WO’961 at 23, citing Chatterjee 2005, explains that LCA induces SULT2A1 expression. It follows that by administering LCA, the activity of the expressed sulfotransferase, SULT2A1, increases. As a result, the amount of LCA administered represents a result effective variable wherein administering more LCA results in more expressed SULT2A1 and observed activity of the sulfotransferase. Therefore, it would take only ordinary and routine experimentation of increasing the amount of LCA administered and benchmarking it against some threshold of “an appropriate control” in order to increase the “the activity of sulfotransferase … by at least 50%” as compared to some “appropriate control”.
Therefore, claim 95 was obvious for the reasons given above, and for the same reasons claim 1 was obvious at the time of filing.
Claims 96-97 were Obvious at the Time of Filing
Claims 96-97 recite:
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Instant claims 96-97.
WO’961, Ferrell 2019, and Chatterjee 2005 are relied upon as above
Regarding claims 96 and 97, the Instant Specification states that SULT2A (recited in claim 96) means SULT2A1 (recited in claim 97). See Specification at 59, paragraph [00215] (“Further, as used herein, "SULT2A" encompasses all isoforms of SULT2A including, but not limited to, SULT2A1.”).
SULT2A1 was discussed throughout the above rejections. As discussed, WO’961 at 23, citing Chatterjee 2005, explains that LCA induces SULT2A1 expression.
Accordingly, claims 96 and 97 were obvious for the reasons given above, and for the same reasons claim 1 was obvious at the time of filing.
Prior Art Cited but not Applied
The prior art made of record and not relied upon is considered pertinent to applicant’s disclosure.
Pols, Thijs WH, et al. "Lithocholic acid controls adaptive immune responses by inhibition of Th1 activation through the Vitamin D receptor." PLoS One 12.5 (2017): e0176715, hereinafter “Pols 2017”.
Teaches that poor health outcomes are correlated with lower serum levels of LCA and suggests confirming the result in larger clinical trials. Working from Pols 2017 alone, it appears obvious to supplement LCA in certain patient populations that have lower serum levels of LCA.
See Pols 2017 at 13/16
Bile acids are well known for their presence within the entero-hepatic cycle. Bile acids can also reach high levels in the peripheral circulation, where concentrations up to 10 μM have been reported in healthy subjects after food intake [2, 3]. LCA is a secondary bile acid that is abundantly present in the portal vein but also found in the peripheral circulation mainly in its unconjugated form, where it can reach concentrations up to 0.5 μM [3]. Interestingly, we observed that LCA already impacts on Th cell inflammation at concentrations of 0.5 μM. This indicates that physiological concentrations of LCA in the peripheral circulation of healthy humans are sufficient to impact on adaptive immune responses.
Bile acids are interlinked to many facets important in atherosclerosis and inflammation. For example, bile acids are part of the cholesterol elimination route and are also heavily dependent on a healthy liver function. This makes the interpretation of correlations between bile acid levels and inflammatory diseases challenging. One small study has revealed a negative correlation between LCA levels and coronary artery disease [44]. Coronary artery disease is driven by atherosclerosis, a chronic inflammatory disease to which Th1-polarized T cells significantly contribute [13]. Our data could potentially indicate that LCA adds to the protection against coronary artery disease by blocking Th1 responses, although this correlation should be confirmed in other (larger) clinical trials. Several other implications of our results also deserve further study, including potential effects on T helper-driven macrophage activation and polarization [45].
LCA is a secondary bile acid and its formation depends on a small population of gut bacteria in the Clostridium genus that express 7α-dehydroxylase [46]. Consequently, antibiotics that affect the gut flora are demonstrated to impact on LCA formation [47]. It is therefore interesting to speculate that diets, antibiotics and pro/prebiotics could possibly modulate adaptive immune responses via the novel LCA-Th cell axis that we here describe.
In conclusion, we demonstrate in Th cells that LCA impedes Th1 activation via the VDR. This is the first time that bile acids are shown to directly impact on adaptive immune responses, an unrecognized action that further expands the hormone-like signaling power of bile acids. Our data may have important implications regarding drug and food strategies that impact on bile acid metabolism, as our data argue that these could potentially impact on adaptive immune responses via a yet unrecognized LCA-Th cell axis.
Pols 2017 at 13/16.
Conclusion
No claims 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.
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/C.E.R./ Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/ Supervisory Patent Examiner, Art Unit 1629
1 The references are the same as those designated in the Non-Final Rejection mailed 03/02/2026.
2 The references are the same as those designated in the Non-Final Rejection mailed 03/02/2026.
3 The Specification at 20, paragraph [0071] explains that inflammatory diseases are serious long-term complications of diabetes. See Specification at 20, paragraph[0071] (“Serious long-term complications (i.e. chronic side effects) include cardiovascular disease (doubled risk), inflammatory diseases, chronic renal failure, retinal damage (which can lead to blindness), nerve damage (of several kinds), and microvascular damage, which may cause impotence and poor wound healing.”).
4 NPCs include hepatic stellate cells (HSCs), myofibroblasts, Kupffer cells (KCs), and sinusoidal endothelial cells (SECs). See WO’961 at 2.
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