DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
2. Applicant’s correspondence filed July 13, 2023 is acknowledged. Claims 1-15 are canceled; claims 16-30 are new and presently are pending.
Information Disclosure Statement
3. The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Specification
4. The use of the term “Ocaliva,” which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Rejections - 35 USC § 112
5. The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 16-30 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicants were in possession of the claimed genus.
A) Claims 16-30 are directed to a method of treating a hepatitis B virus (HBV) infection in a subject comprising administering a farnesoid X receptor (FXR) agonist in combination with an interferon alpha (IFN-a), wherein the FXR agonist and IFN-a are administered so as to obtain a synergistic effect for decreasing HBV replication and wherein the FXR agonist is not EYP001. The claims further recite species of FXR agonists and INF-a, dosing schedules, routes of administration, species of additional active ingredients, and administration of sub-therapeutic amounts of the FXR agonists and INF-a (e.g., claims 23 and 25).
The specification defines “synergistic effect” as: "’a synergistic effect’ is intended to refer to an effect for decreasing the HBV replication which is more than the sum of the effects of each molecule alone. HBV replication can be assessed by determining surface HBV antigen (HBsAg).” Specification at page 7, lines 7-9. The Specification further discloses three experiments demonstrating the co-administration of a non-EYP001 FXR agonist and INF-a: FIG. 3 (showing measurements of HBV RNA, viremia, HBsAg, and HBeAg for PHH cells infected with HBV-D and treated from days 4-10 with 100 IU/ml IFN-a, FRX agonist GW4064 at 1 and 10 µM, and combined treatment); FIG. 4 (showing measurements of HBsAg for PHH cells infected with HBV-D and treated from days 4-10 with 100 IU/ml IFN-a, FRX agonist Vonafexor (i.e., EYP101) at 10 µM, Nidufexor at 10 µM, or Tropifexor at 1 µM, or OCA at 10 µM, or GW4064 at 10 µM, and combined treatment); and FIG. 5 (showing measurements of HBsAg for dHepaRG cells infected with HBV-D and treated from days 7-14 with 25 IU/ml IFN-a, FRX agonist Vonafexor (i.e., EYP101) at 10 µM, Nidufexor at 10 µM, or Tropifexor at 1 µM, or OCA at 10 µM, or GW4064 at 10 µM, and combined treatment). A close inspection of the data presented in these figures reveals that all of the combined treatments show merely additive effects, other than the HBsAg measurement shown in FIG. 3 achieved with FXR agonist GW4064 combined with IFN-a. This data shows supra-additive effects because it shows IFN-a alone reduced HBsAg by approximately 10% compared to control, GW4064 alone at 1 or 10 µM had negligible effects on HBsAg compared to control, but the combined treatment resulted in 40-60% decreases in HBsAg. This is “more than the sum of the effects of each molecule alone.” No other data presented in the instant specification shows such an effect for a non-EYP001 FXR agonist combined with IFN-a; the remaining results show merely additive effects that do not constitute “synergistic effects” according to the definition for synergistic effect provided by Applicant and the broadest reasonable interpretation of the term.
Regarding “sub-therapeutic amount,” the specification again provides a definition: “’sub-therapeutic amount’ or ‘sub-therapeutic dose’ refers to a dosage which is less than that dosage which would produce a therapeutic result in the subject if administered in the absence of the other agent. For instance, ‘sub-therapeutic amount’ or ‘sub-therapeutic dose’ can refer to a dosage which is decreased by 25, 50, 70, 80 or 90 % in comparison to the therapeutically effective amount, especially the conventional therapeutic dosage for the same indication and the same administration route when used alone. The conventional therapeutic dosages are those acknowledged by the drug approvals agencies (e.g., FDA or EMEA)” Specification at page 6, lines 27-33. The specification further defines therapeutic result/effect: “’therapeutic effect’ refers to an effect induced by an active ingredient, or a pharmaceutical composition according to the invention, capable to prevent or to delay the appearance or development of a disease or disorder, or to cure or to attenuate the effects of a disease or disorder. As used herein, the term ‘therapeutically effective amount’ refers to a quantity of an active ingredient or of a pharmaceutical composition which prevents, removes or reduces the deleterious effects of the disease, particularly infectious disease.” Specification at page 6, lines 17-19. Therefore, a sub-therapeutic amount according to the specification should not include a dose that (i) attenuates the effects of a disease and/or (ii) reduces the deleterious effects of the disease.
The specification only provides examples of non-EYP001 FXR agonist and IFN-a doses: Nidufexor administered at 10 µM, Tropifexor administered at 1 µM, OCA administered at 10 µM, GW4064 administered at 1 or 10 µM; and IFN-a administered at 100 IU/ml (e.g., FIGs. 3-4, administered to PHH cells) or at 25 IU/ml (e.g., FIG. 5, administered to dHepaRG cells). However, the specification’s experimental data reveals that administration of these compounds at the specified doses had therapeutic effect as measured by HBsAg secretion measurements, other than possibly GW4064 administered at 1 µM. For example, all the non-EYP001 FXR agonists, administered alone, reduced HBsAg secretion by 25-50% in FIGs. 4 and 5, and IFN-a alone also reduced HBsAg secretion by 25-50% in these figures. Although FIG. 3 (which uses the same methods as FIG. 4) does not tightly accord with the data presented in the other figures—e.g., 10 µM GW4064 alone is shown to have negligible effects on HBsAg secretion—FIG. 4 clearly shows the therapeutic effect of 10 µM GW4064. Therefore, to the extent applicant has demonstrated a “sub therapeutic amount” of any non-EYP001 FXR agonist and/or INF-a, it is only possibly by the use of 1 µM GW4064 at FIG. 3.
The specification therefore provides insufficient guidance regarding how to obtain a “synergistic effect” for the broad genus of FXR agonists claimed because the examples suggest GW4064 was the only non-EYP101 FXR agonist of the four tested to achieve synergism with (a therapeutic) IFN-a dose. Accordingly, the specification provides insufficient written description to support the genus of FXR agonists administered to achieve synergism with IFN-a encompassed by the claims.
The specification also provides insufficient written description to support the genus of FXR agonist and IFN-a “sub-therapeutic” doses encompassed by the claims (e.g., claims 23 and 25). Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that:
"applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
The claims recite “sub-therapeutic” amounts of IFN-a or FXR agonist at claims 23 and 25, but the claims and the specification do not explicitly describe what dosage or concentration of IFN-a or FXR agonist is needed to achieve the “sub-therapeutic” amount. To address this issue, a brief assessment of the state of the art regarding sub-therapeutic doses is made herein, specifically how the concentrations of the IFN-a and FXR agonists demonstrated in the specification compare to their EC50 values, the concentration where IFN-a and FXR agonists will obtain their half-maximal effective concentration. Panzitt et al. ("Recent advances on FXR-targeting therapeutics." Molecular and Cellular Endocrinology 552 (2022): 111678) teaches that the EC50 (half-maximal effective concentration) values for the non-EYP101 FXR agonists demonstrated in the instant specification are: Nidufexor (7 nM), Tropifexor (0.2 nM), OCA (100 nM), and GW4064 (40 nM). Panzitt et al. at Table 1. The instant specification discloses treatment of HBV-D infected PHH and/or dHepaRG cells with Nidufexor at 10 µM, Tropifexor at 1 µM, OCA at 10 µM, and GW4064 at 1 or 10 µM. Accordingly, the cells were treated with Nidufexor at 1,428x, Tropifexor at 50,000x, OCA at 100x, and GW4064 at 25x or 250x the respective EC50 values for these FXR agonists. A skilled person would readily recognize these to be high doses, not “sub-therapeutic” doses. Furthermore, Shen et al. ("Hepatitis B virus sensitivity to interferon‐α in hepatocytes is more associated with cellular interferon response than with viral genotype." Hepatology 67.4 (2018): 1237-1252) teaches EC50 values of INF-a for treating HBV-D (using PHH and dHepaRG models nearly identical to those used by Applicant) to be 198.6 IU/ml for 9 days of treatment of PHH cells; and 59.2 IU/ml for 9 days of treatment of dHepaRG cells. See Shen et al. at Table 1. For example, the PHH cells treated with 100 IU/ml showed a similar reduction of HBsAg secretion as disclosed in the instant specification. See Shen et al. at FIG. 2B. Therefore, although the instant application discloses treatment with IFN-a below the EC 50 value—in contrast to the presently disclosed treatment with the FXR agonists at a concentration well above the EC50 values—Shen et al. corroborates that, e.g., 100 IU/ml IFN-a in PHH cells significantly reduces HBsAg secretion, and therefore is therapeutic within the meaning of Applicant’s specification. Therefore, the instant specification fails to disclose a single species of sub-therapeutic dose of FXR agonist or IFN-a.
Additionally, the PEGASYS (IFN-a) FDA label (accessdata.fda.gov/drugsatfda_docs/label/ 2011/103964s5204lbl.pdf, revised September 2011) shows that a dose can be reduced below optimal levels and remain therapeutically effective within the meaning of the instant specification. Therefore, although the specification also defines “sub-therapeutic amount” as: “’sub-therapeutic amount’ or ‘sub-therapeutic dose’ refers to a dosage which is less than that dosage which would produce a therapeutic result in the subject if administered in the absence of the other agent. For instance, ‘sub-therapeutic amount’ or ‘sub-therapeutic dose’ can refer to a dosage which is decreased by 25, 50, 70, 80 or 90 % in comparison to the therapeutically effective amount, especially the conventional therapeutic dosage for the same indication and the same administration route when used alone. The conventional therapeutic dosages are those acknowledged by the drug approvals agencies (e.g., FDA or EMEA)” (specification at page 6, lines 27-33), the FDA label suggests these decreased dosages still retain some therapeutically effect. More specifically, the FDA label discloses a conventional dosage of pegylated INF-a for treating HBV of 180 mcg, but the label also recommends reducing the dose to 135 mcg (e.g., 75% of the conventional therapeutic dose) or 90 mcg (e.g., 66.6% of the conventional therapeutic dose) if “adverse reactions” are encountered. PEGASYS FDA label at page. Therefore, the FDA label suggests that “sub-therapeutic” doses retain therapeutic effects, similar to the effects demonstrated in the instant specification by using 25 or 100 IU/ml IFN-a (e.g., these doses of IFN-a had significant effects on HBsAg section as shown at instant FIGs. 3-5).
It would not have been apparent to one skilled in the art that administering any FXR agonist may obtain a synergistic effect with IFN-a, let alone that synergy can be obtained by using “sub-therapeutic” doses of any FXR agonist and IFN-a. Applicant has not established any nexus between the synergistic effects on HBsAg secretion between a therapeutic dose of IFN-a and a possibly sub-therapeutic dose of GW4064 (e.g., 1 µM GW4064 at FIG. 3) that merits extrapolation of synergistic effects / sub-therapeutic doses to IFN-a and FRX agonists in general, especially in view of the data present in the specification at FIGs. 4 and 5, which demonstrates a lack of synergism between all four non-EYP001 FRX agonists tested with IFN-a.
Therefore, neither the art nor the specification provides a sufficient representative number of FXR agonists and/or IFN-a administered at sub-therapeutic doses or having synergistic effects to meet the written description requirement for instant claims directed to the genus of non-EYP001 FXR agonists synergistic with IFN-a in general.
B) Claims 16-30 are directed to a method of treating a hepatitis B virus (HBV) infection in a subject comprising administering a farnesoid X receptor (FXR) agonist in combination with an interferon alpha (IFN-a), wherein the FXR agonist and IFN-a are administered so as to obtain a synergistic effect for decreasing HBV replication and wherein the FXR agonist is not EYP001. The claims further recite the FXR agonist may be Fexaramine (e.g., claim 17). The claims therefore encompass any FXR agonist presently known or developed in the future.
The specification indicates that “the primary goal of treatment for chronic hepatitis B (CHB) is to permanently suppress HBV replication and prevent or improve liver disease.” Specification at page 1, lines 10-11. The specification further discloses models only using PHH and dHerpaRG cells (i.e., liver cells) to demonstrate therapeutic effects of FXR agonists administered in combination with IFN-a. See e.g., FIGs. 3-5. The specification further discloses in these figures the co-administration of only four non-EYP001 FXR agonists and/or INF-a: FIG. 3 (showing measurements of HBV RNA, viremia, HBsAg, and HBeAg for PHH cells infected with HBV-D and treated from days 4-10 with 100 IU/ml IFN-a, FRX agonist GW4064 at 1 and 10 µM, and combined treatment); FIG. 4 (showing measurements of HBsAg for PHH cells infected with HBV-D and treated from days 4-10 with 100 IU/ml IFN-a, FRX agonist Vonafexor (i.e., EYP101) at 10 µM, Nidufexor at 10 µM, or Tropifexor at 1 µM, or OCA at 10 µM, or GW4064 at 10 µM, and combined treatment); and FIG. 5 (showing measurements of HBsAg for dHepaRG cells infected with HBV-D and treated from days 7-14 with 25 IU/ml IFN-a, FRX agonist Vonafexor (i.e., EYP101) at 10 µM, Nidufexor at 10 µM, or Tropifexor at 1 µM, or OCA at 10 µM, or GW4064 at 10 µM, and combined treatment). The specification therefore fails to demonstrate the effects of any non-EYP001 FXR agonist other than GW4064, Nidufexor, Tropifexor, or OCA, let alone Fexaramine as instantly recited at claim 17.
The specification therefore provides insufficient guidance regarding how to treat HBV infection (i.e., a liver disease) with the broad genus of FXR agonists instantly claimed because the claim-recited FXR agonist genus includes FXR agonists that are inoperable with the invention (e.g., Fexaramine, a gut-restricted FXR agonists). Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that:
"applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
First, a brief assessment of the state of the art regarding Fexaramine is made herein. Dąbrowska et al. ("Fexaramine as the intestine-specific farnesoid X receptor agonist: A promising agent to treat obesity and metabolic disorders." Drug Discovery Today (2025): 104386) teaches: “Fexaramine, a gut-restricted farnesoid X receptor (FXR) agonist, promotes glucose and lipid homeostasis, improves insulin sensitivity, promotes white adipose tissue browning, and stimulates nonshivering thermogenesis. Enhancement in energy expenditure due to an increase in amount of energy burned by brown and ‘beige’ adipocytes results in subsequent weight loss. Fexaramine is poorly absorbed into circulation when delivered orally, which limits systemic FXR activation and toxicity. An increase in β3-adrenoceptor signaling, activation of Takeda G protein-coupled receptor 5/glucagon-like peptide-1 (TGR5/GLP-1) signaling, and induction of fibroblast growth factor (FGF)-19/FGF-15 play crucial roles in fexaramine metabolic actions. Intestinal FXR activation is a promising, potentially safe approach for treating obesity and metabolic syndrome.” Dąbrowska et al. at abstract. Debrowska et al. therefore teaches effects of Fexaramine having intestinal origin.
Furthermore, Dabrowka et al. teaches “in contrast to the systemic agonism of FXR, fexaramine does not activate FXR genes in the liver, resulting in intestinally restricted FXR activation.” Dabrowka et al. at Fexaramine: The intestine‐specific FXR agonist, without systemic FXR activation. However, it is well known that HBV is a liver specific disease. See CDC HBV fact sheet at About Hepatitis B (e.g., “Hepatitis B is a vaccine-preventable liver infection caused by HBV”). Therefore, it is not reasonably believable that the claim-recited Fexaramine could be used to treat the liver-infection etiology of HBV infection in a subject, as recited by the claims.
A further brief assessment of the state of the art regarding the differences in tissue specificity and potential side effects of FXR agonists in general is made herein. Panzitt et al. teaches: “Various FXR agonists with different physicochemical properties exist, which can broadly be sub-classified into ones with a steroidal or non-steroidal scaffold. […] Due to their different structure and physicochemical properties these agonists differ in various aspects: the potency to activate FXR as full or partial agonist, the specificity to other receptors in particular TGR5, the bioavailability which determines their capacity to act on intestinal > hepatic FXR, the enterohepatic cycling and the affinity for different cellular uptake transporters. Of note, plasma concentrations of FXR ligands are not predictive of the potency of FXR agonists, and liver concentrations of FXR ligands do not necessarily correlate directly with FXR activity. Moreover, liver residency time may be far longer than plasma lifetime. The best method to test the potential of the novel compound for hepatic and or intestinal FXR activity should be by addressing direct gene expression analysis in vivo. Although many of the various structurally leading compounds have been tested in in vivo models or even clinical trials, a thorough head-to-head comparison in a comparable fashion is often lacking. […] critical information on hepatobiliary enrichment versus plasma enrichment and their genome-wide transcriptomic profile is largely missing. This is important information because very likely transcriptomic profiles vary among different ligands. In fact, very early comparative experiments indicate that with the exception of consensus FXR target genes, broader gene expression patterns among different FXR agonists – in that particular study CDCA, fexaramine and GW4064 – are strikingly different. More recently, a comparable transcriptomic analysis among two structurally different FXR agonists showed a clear separation in principal component analysis. Since FXR ligands likely do not alter DNA binding on cistromic levels but mainly transcriptional events, differences in gene transcription may be primarily caused by conformational changes after binding of different ligands and subsequently different co-regulator recruitment.” Panzitt et al. at “Therapeutic potential of steroidal and non-steroidal FXR agonists” (internal citations omitted). Therefore, FXR agonists in general have different bioavailability to the liver, and different effects of gene expression, and this will have a great effect on any FXR agonist’s ability to treat HBV infection in a subject.
Panzitt et al. also further teaches: “Restriction of FXR to specific target tissues may increase pharmacologically wanted effects and limit side effects. The main tissue sites which are especially targeted are either the intestine or the liver. […] Only a minority of FXR binding sites are overlapping between the liver and the intestine. […] Moreover, FXR isoforms are differentially prevalent in various tissues (e.g. liver, intestine, kidney), which then also show different responses to FXR agonistic treatment. Pharmacologically, tissue specificity can be achieved by modulating the physicochemical properties of the FXR ligands, which critically depends on the uptake by bile specific transporter systems in the liver or intestine (see above) and the residence time of a ligand in a specific tissue. Examples of FXR ligands with intestine specificity include fexaramine, TC-100 and ivermectin. So far, there is no exclusive liver specific FXR agonist known. In general, the non-steroidal FXR agonists show an intestinal preponderance.” Panzitt et al. at “Partial agonists/selective agonists for FXR” (internal citations omitted). Therefore, it is not reasonably believable that any FXR agonist may be used to treat HBV infection in a subject because many FXR agonists will also have unacceptable levels of side effects for this purpose.
It would not have been apparent to one skilled in the art that administering any FXR agonist may beneficially treat HBV infection, a liver disease, let alone that the FXR agonist Fexaramine—a gut-restricted FXR agonist—may beneficially treat HBV infection. Applicant has not established any nexus between the laundry list of FXR agonists recited in the specification and claims (e.g., including Fexaramine) and the beneficial effects on HBV infection demonstrated at FIGs. 3-5, which were obtained by specifically using Nidufexor, Tropifexor, OCA, or GW4064.
As a further example of the unpredictability in using any FXR agonist, GW4064—the non-EPY001 FXR agonist most extensively used in Applicant’s specification—too is known to have unpredictable effectiveness for threating HBV infection. As demonstrated by Mouzannar et al. ("Farnesoid X receptor‐α is a proviral host factor for hepatitis B virus that is inhibited by ligands in vitro and in vivo." The FASEB Journal 33.2 (2019): 2472-2483), HBV infected mice receiving oral gavage of 50 mg/kg/d GW4064 had a significant effect on serum HBsAg titers only in adult mice, with no effects observed in juvenile mice. See Mouzannar et al. at FIG. 6. Therefore, the predictability in using any FXR agonist to treat HBV infection is low since there is a lack of predictability even with GW4064, a well-known FXR agonist for testing HBV infection therapeutics.
Erken et al. ("Farnesoid X receptor agonist for the treatment of chronic hepatitis B: a safety study." Journal of viral hepatitis 28.12 (2021): 1690-1698) correctly summarized the state of the art regarding the use of any FXR agonist for the treatment of HBV infection: “[w]e hypothesized that Vonafexor [EYP001], a novel synthetic, orally active, non‐bile salt, non‐steroidal, carboxylic acid selective FXR agonist, may reduce the viral transcription activity in CHB patients. Vonafexor was identified in vitro as highly selective for FXR relative to other FXR agonists (e.g., GS9674, GW4064 and Ocaliva) and with properties better suited to clinical development. Moreover, Vonafexor has been shown to be less potent than alternative compounds, which would support the safe long‐term use in patients while maintaining an appropriate balance between its anti‐HBV activity and its metabolic effects” (Erken et al. at introduction; the negative limitation in the claims regarding EYP001 is acknowledged and appreciated by the Office, and so this statement regarding EYP001 is being used solely to highlight the lack of predictability regarding the use of any FXR agonists for the treatment of HBV infection). Therefore, not all FXR agonists are well suited for the treatment of HBV infections.
Neither the art nor the specification provides a sufficient representative number of FXR agonists to meet the written description requirement for instant claims directed to the broad genus of non-EYP001 FXR agonists in general.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, 'does the description clearly allow person of ordinary skill in the art to recognize that he or she invented what is claimed’”. The courts have decided: the purpose of the "written description" requirement is broader than to merely explain how to "make and use"; the Applicant must convey with reasonable clarity to those skilled in the art, that as of the filing date sought, he or she was in possession of the invention. The invention is for purposes of the “written description” inquiry, whatever is now claimed. See Vas-Cath, Inc v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991).
Furthermore, the written description provision of 35 USC §112 is severable from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993). And Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Moreover, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has the Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed.
Therefore, for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
6. 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 17 and 18 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.
Claims 17 and 18 contain the trademark/trade name “Ocaliva.” Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. n the present case, the trademark/trade name is used to identify/describe the FXR agonist and, accordingly, the identification/description is indefinite.
Claim Rejections - 35 USC § 102
7. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
8. Claims 16-19 and 21-30 are rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Andre et al. (WO 2015/036442 A1, published March 19, 2015).
Claim 16 is drawn to a method of treating a hepatitis B virus (HBV) infection in a subject comprising administering a farnesoid X receptor (FXR) agonist in combination with an interferon alpha (IFN-a), wherein the FXR agonist and IFN-a are administered so as to obtain a synergistic effect for decreasing HBV replication and wherein the FXR agonist is not EYP001.
Claim 17 is drawn to the method according to claim 16, wherein the FXR agonist is selected from the group consisting of LJN452 (Tropifexor), LMB763 (Nidufexor), GS-9674 (Cilofexor), PX-102 (PX-20606), PX-104 (Phenex 104), OCA (Ocaliva), EDP-297, EDP-305, TERN-101 (LY2562175), MET-409, MET-642, GW4064, WAY362450 (Turofexorate isopropyl), Fexaramine, AGN242266 (AKN-083), and BAR502 or any pharmaceutically acceptable salt thereof.
Claim 18 is drawn to the method according to claim 16, wherein the FXR agonist is selected from the group consisting of Tropifexor, Nidufexor, Ocaliva and GW4064, or any pharmaceutically acceptable salt thereof.
Claim 19 is drawn to the method according to claim 16, wherein the FXR agonist is administered once a day.
Claim 21 is drawn to the method according to claim 16, wherein the IFN-a is IFN-a2a, IFN-a2b or a pegylated form thereof.
Claim 22 is drawn to the method according to claim 16, wherein the IFN-a is a pegylated IFN- a2a or a pegylated IFN-a2b.
Claim 23 is drawn to the method according to claim 16, wherein the IFN-a is administered at a sub-therapeutic amount.
Claim 24 is drawn to the method according to claim 16, wherein the IFN-a is administered by a subcutaneous route once a week.
Claim 25 is drawn to the method according to claim 16, wherein the FXR agonist is administered at a sub-therapeutic amount.
Claim 26 is drawn to the method according to claim 16, wherein the HBV infection is chronic hepatitis B infection.
Claim 27 is drawn to the method according to claim 16, wherein the FXR agonist and the IFN-a are administered during a period of time from 5, 6, 7 or 8 weeks to 52 weeks.
Claim 28 is drawn to the method according to claim 16, wherein the FXR agonist and the IFN-a are administered in combination with at least one additional active ingredient.
Claim 29 is drawn to the method according to claim 28, wherein the at least one additional active ingredient is a polymerase inhibitor selected from the group consisting of L-nucleosides, deoxyguanosine analogs and nucleoside phosphonates.
Claim 30 is drawn to the method according to claim 28, wherein the at least one additional active ingredient is selected from the group consisting of lamivudine, telbivudine, emtricitabine, entecavir, adefovir and tenofovir.
Andre et al. teaches the treatment of hepatitis B (HBV) infection comprising administering a farnesoid X receptor (FXR) agonist wherein the FXR agonists is not EPY001 See Andre et al. at Abstract. Andre et al. also teaches the FXR agonist can be administered in combination with IFN-a, e.g., “the FXR agonist according to the invention may be administered to the subject in combination with currently available therapy, including treatment with antiviral drugs such as the reverse transcriptase inhibitors, lamivudine (Epivir), adefovir (Hepsera), tenofovir (Viread), telbivudine (Tyzeka) and entecavir (Baraclude), and such as immune system modulators, interferon alpha-2a, PEGylated interferon alpha-2a (Pegasys) or interferon alpha-2b (ViraferonPeg ou Introna)” (claim 16). Andre et al. at page 52, lines 10-15. Andre et al. also lists many suitable FXR agonists other than EPY001, including GW4064 (claims 17-18). Andre et al. at page 11, line 26. As shown above, Andre et al. also discloses pegylated interferons (claims 21-22). Andre et al. therefore teaches Applicant’s invention—administering an FXR agonist in combination with an IFN-a to treat HBV. Andre et al. teaches daily dosage of the FXR agonist, which necessarily includes administering the FXR agonist at least once a day, e.g., “the daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per adult per day.” Andre et al. at page 51, lines 23-24 (claim 19). Andre et al. teaches administration of sub-therapeutic amounts of IFN-a and/or FXR agonist, e.g., “[t]he phrase ‘induction regimen’ or ‘induction period’ refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the initial treatment of a disease. The general goal of an induction regimen is to provide a high level of drug to a patient during the initial period of a treatment regimen. An induction regimen may employ (in part or in whole) a "loading regimen", which may include administering a greater dose of the drug than a physician would employ during a maintenance regimen, administering a drug more frequently than a physician would administer the drug during a maintenance regimen, or both. The phrase ‘maintenance regimen’ or ‘maintenance period’ refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the maintenance of a patient during treatment of an illness, e.g., to keep the patient in remission for long periods of time (months or years). A maintenance regimen may employ continuous therapy (e.g., administering a drug at a regular intervals, e.g., weekly, monthly, yearly, etc.) or intermittent therapy (e.g., interrupted treatment, intermittent treatment, treatment at relapse, or treatment upon achievement of a particular predetermined criteria [e.g., pain, disease manifestation, etc.]).” Andre et al. at pages 4-5, lines 27-7. Since Andre et al. teaches “partial” and “intermittent” dosing of the therapeutics, it teaches “sub-therapeutic” amounts of the therapeutics in view of the instant specification, which states that a “sub-therapeutic amount” can refer to a dosage decreased by various amounts compared to the conventional dose (see instant specification at page 6, lines 27-33; claims 23 and 25). Andre et al. teaches that the IFN-a can be administered by a subcutaneous route once a week, e.g., “the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration, the active principle, alone or in combination with another active principle, can be administered in a unit administration form, as a mixture with conventional pharmaceutical supports, to animals and human beings” and “[a] maintenance regimen may employ continuous therapy (e.g., administering a drug at a regular intervals, e.g., weekly, monthly, yearly, etc.).” Andre et al. at page 52, lines 27-31; page 4, lines 3-5 (claim 24). Andre et al. teaches that the HBV infection is chronic hepatitis B infection, e.g., “In some embodiments, the subject suffers from a chronic HBV infection.” Andre et al. at page 4, lines 14-15 (claim 26). Andre et al. teaches the FXR agonist and the IFN-a can be administered during a period of time from 5, 6, 7 or 8 weeks to 52 weeks, e.g., “HBV DNA (IU/mL) can be measured at regular intervals during the treatment, e.g., at Day 1 (pre-dose and 4, 8, and 12 hours post-dose) and pre-dose at Day 2, Day 3, Day 8, Day 15, Day 29, and at Week 12, Week 24, Week 36, Week 48, Week 72 (when applicable), and at follow up.” Andre et al. at page 4, lines 12-15 (claim 27). Andre et al. teaches the administration of additional active ingredients (claim 28), wherein the at least one additional active ingredient is a polymerase inhibitor selected from the group consisting of L-nucleosides, deoxyguanosine analogs and nucleoside phosphonates (claim 29), and wherein the at least one additional active ingredient is selected from the group consisting of lamivudine, telbivudine, emtricitabine, entecavir, adefovir and tenofovir (claim 30), e.g., “the FXR agonist according to the invention may be administered to the subject in combination with currently available therapy, including treatment with antiviral drugs such as the reverse transcriptase inhibitors, lamivudine (Epivir), adefovir (Hepsera), tenofovir (Viread), telbivudine (Tyzeka) and entecavir (Baraclude), and such as immune system modulators, interferon alpha-2a, PEGylated interferon alpha-2a (Pegasys) or interferon alpha-2b (ViraferonPeg ou Introna).” Andre et al. at page 52, lines 10-15. Andre et al. also further teaches that: “the primary goal of treatment for chronic hepatitis B (CHB) is to permanently suppress HBV replication and prevent or improve liver disease. Seven drugs are currently available for treatment of CHB infection - conventional interferon, pegylated interferon and direct antiviral agents. The direct antivirals (nucleos/tide analogues) belong to three classes: L-nucleosides (lamivudine, telbivudine and emtricitabine); deoxyguanosine analogue (entecavir) and nucleoside phosphonates (adefovir and tenofovir) which directly interfere with HBV DNA replication, primarily as chain terminators. Andre et al. at page 1, lines 27-33. Andre et al. teaches a method of treating a hepatitis B virus (HBV) infection in a subject comprising administering a farnesoid X receptor (FXR) agonist in combination with an interferon alpha (IFN-a), which is the same method as taught by the claimed invention (e.g., claim 16). Therefore, the claim limitation “wherein the FXR agonist and IFN-a are administered so as to obtain a synergistic effect for decreasing HBV replication and wherein the FXR agonist is not EYP001” is taught by Andre et al. Andre et al. therefore anticipates the claimed invention.
Claim Rejections - 35 USC § 103
9. 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.
10. 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.
11. Claims 16-30 are rejected under 35 U.S.C. 103 as being unpatentable over Andre et al. (WO 2015/036442 A1, published March 19, 2015) in view of Pruzanski et al. (WO 2016/164413 A1, published October 13, 2016).
Claim 16 is drawn to a method of treating a hepatitis B virus (HBV) infection in a subject comprising administering a farnesoid X receptor (FXR) agonist in combination with an interferon alpha (IFN-a), wherein the FXR agonist and IFN-a are administered so as to obtain a synergistic effect for decreasing HBV replication and wherein the FXR agonist is not EYP001.
Claim 17 is drawn to the method according to claim 16, wherein the FXR agonist is selected from the group consisting of LJN452 (Tropifexor), LMB763 (Nidufexor), GS-9674 (Cilofexor), PX-102 (PX-20606), PX-104 (Phenex 104), OCA (Ocaliva), EDP-297, EDP-305, TERN-101 (LY2562175), MET-409, MET-642, GW4064, WAY362450 (Turofexorate isopropyl), Fexaramine, AGN242266 (AKN-083), and BAR502 or any pharmaceutically acceptable salt thereof.
Claim 18 is drawn to the method according to claim 16, wherein the FXR agonist is selected from the group consisting of Tropifexor, Nidufexor, Ocaliva and GW4064, or any pharmaceutically acceptable salt thereof.
Claim 19 is drawn to the method according to claim 16, wherein the FXR agonist is administered once a day.
Claim 20 is drawn to the method according to claim 16, wherein the FXR agonist is administered twice a day.
Claim 21 is drawn to the method according to claim 16, wherein the IFN-a is IFN-a2a, IFN-a2b or a pegylated form thereof.
Claim 22 is drawn to the method according to claim 16, wherein the IFN-a is a pegylated IFN- a2a or a pegylated IFN-a2b.
Claim 23 is drawn to the method according to claim 16, wherein the IFN-a is administered at a sub-therapeutic amount.
Claim 24 is drawn to the method according to claim 16, wherein the IFN-a is administered by a subcutaneous route once a week.
Claim 25 is drawn to the method according to claim 16, wherein the FXR agonist is administered at a sub-therapeutic amount.
Claim 26 is drawn to the method according to claim 16, wherein the HBV infection is chronic hepatitis B infection.
Claim 27 is drawn to the method according to claim 16, wherein the FXR agonist and the IFN-a are administered during a period of time from 5, 6, 7 or 8 weeks to 52 weeks.
Claim 28 is drawn to the method according to claim 16, wherein the FXR agonist and the IFN-a are administered in combination with at least one additional active ingredient.
Claim 29 is drawn to the method according to claim 28, wherein the at least one additional active ingredient is a polymerase inhibitor selected from the group consisting of L-nucleosides, deoxyguanosine analogs and nucleoside phosphonates.
Claim 30 is drawn to the method according to claim 28, wherein the at least one additional active ingredient is selected from the group consisting of lamivudine, telbivudine, emtricitabine, entecavir, adefovir and tenofovir.
Andre et al. teaches the treatment of hepatitis B (HBV) infection comprising administering a farnesoid X receptor (FXR) agonist wherein the FXR agonists is not EPY001. See Andre et al. at Abstract. Andre et al. also teaches the FXR agonist can be administered in combination with IFN-a, e.g., “the FXR agonist according to the invention may be administered to the subject in combination with currently available therapy, including treatment with antiviral drugs such as the reverse transcriptase inhibitors, lamivudine (Epivir), adefovir (Hepsera), tenofovir (Viread), telbivudine (Tyzeka) and entecavir (Baraclude), and such as immune system modulators, interferon alpha-2a, PEGylated interferon alpha-2a (Pegasys) or interferon alpha-2b (ViraferonPeg ou Introna)” (claim 16). Andre et al. at page 52, lines 10-15. Andre et al. also lists many suitable FXR agonists other than EPY001, including GW4064 (claims 17-18). Andre et al. at page 11, line 26. As shown above, Andre et al. also discloses pegylated interferons (claims 21-22). Andre et al. therefore teaches Applicant’s invention—administering an FXR agonist in combination with an IFN-a to treat HBV. Andre et al. teaches daily dosage of the FXR agonist, which necessarily includes administering the FXR agonist at least once a day, e.g., “the daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per adult per day.” Andre et al. at page 51, lines 23-24 (claim 19). Andre et al. teaches administration of sub-therapeutic amounts of IFN-a and/or FXR agonist, e.g., “[t]he phrase ‘induction regimen’ or ‘induction period’ refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the initial treatment of a disease. The general goal of an induction regimen is to provide a high level of drug to a patient during the initial period of a treatment regimen. An induction regimen may employ (in part or in whole) a "loading regimen", which may include administering a greater dose of the drug than a physician would employ during a maintenance regimen, administering a drug more frequently than a physician would administer the drug during a maintenance regimen, or both. The phrase ‘maintenance regimen’ or ‘maintenance period’ refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the maintenance of a patient during treatment of an illness, e.g., to keep the patient in remission for long periods of time (months or years). A maintenance regimen may employ continuous therapy (e.g., administering a drug at a regular intervals, e.g., weekly, monthly, yearly, etc.) or intermittent therapy (e.g., interrupted treatment, intermittent treatment, treatment at relapse, or treatment upon achievement of a particular predetermined criteria [e.g., pain, disease manifestation, etc.]).” Andre et al. at pages 4-5, lines 27-7. Since Andre et al. teaches “partial” and “intermittent” dosing of the therapeutics, it teaches “sub-therapeutic” amounts of the therapeutics in view of the instant specification, which states that a “sub-therapeutic amount” can refer to a dosage decreased by various amounts compared to the conventional dose (see instant specification at page 6, lines 27-33; claims 23 and 25). Andre et al. teaches that the IFN-a can be administered by a subcutaneous route once a week, e.g., “the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration, the active principle, alone or in combination with another active principle, can be administered in a unit administration form, as a mixture with conventional pharmaceutical supports, to animals and human beings” and “[a] maintenance regimen may employ continuous therapy (e.g., administering a drug at a regular intervals, e.g., weekly, monthly, yearly, etc.).” Andre et al. at page 52, lines 27-31; page 4, lines 3-5 (claim 24). Andre et al. teaches that the HBV infection is chronic hepatitis B infection, e.g., “In some embodiments, the subject suffers from a chronic HBV infection.” Andre et al. at page 4, lines 14-15 (claim 26). Andre et al. teaches the FXR agonist and the IFN-a can be administered during a period of time from 5, 6, 7 or 8 weeks to 52 weeks, e.g., “HBV DNA (IU/mL) can be measured at regular intervals during the treatment, e.g., at Day 1 (pre-dose and 4, 8, and 12 hours post-dose) and pre-dose at Day 2, Day 3, Day 8, Day 15, Day 29, and at Week 12, Week 24, Week 36, Week 48, Week 72 (when applicable), and at follow up.” Andre et al. at page 4, lines 12-15 (claim 27). Andre et al. teaches the administration of additional active ingredients (claim 28), wherein the at least one additional active ingredient is a polymerase inhibitor selected from the group consisting of L-nucleosides, deoxyguanosine analogs and nucleoside phosphonates (claim 29), and wherein the at least one additional active ingredient is selected from the group consisting of lamivudine, telbivudine, emtricitabine, entecavir, adefovir and tenofovir (claim 30), e.g., “the FXR agonist according to the invention may be administered to the subject in combination with currently available therapy, including treatment with antiviral drugs such as the reverse transcriptase inhibitors, lamivudine (Epivir), adefovir (Hepsera), tenofovir (Viread), telbivudine (Tyzeka) and entecavir (Baraclude), and such as immune system modulators, interferon alpha-2a, PEGylated interferon alpha-2a (Pegasys) or interferon alpha-2b (ViraferonPeg ou Introna).” Andre et al. at page 52, lines 10-15. Andre et al. also further teaches that: “the primary goal of treatment for chronic hepatitis B (CHB) is to permanently suppress HBV replication and prevent or improve liver disease. Seven drugs are currently available for treatment of CHB infection - conventional interferon, pegylated interferon and direct antiviral agents. The direct antivirals (nucleos/tide analogues) belong to three classes: L-nucleosides (lamivudine, telbivudine and emtricitabine); deoxyguanosine analogue (entecavir) and nucleoside phosphonates (adefovir and tenofovir) which directly interfere with HBV DNA replication, primarily as chain terminators. Andre et al. at page 1, lines 27-33. Andre et al. teaches a method of treating a hepatitis B virus (HBV) infection in a subject comprising administering a farnesoid X receptor (FXR) agonist in combination with an interferon alpha (IFN-a), which is the same method as taught by the claimed invention (e.g., claim 16). Therefore, the claim limitation “wherein the FXR agonist and IFN-a are administered so as to obtain a synergistic effect for decreasing HBV replication and wherein the FXR agonist is not EYP001” is taught by Andre et al. Andre et al. teaches optimized doses of the FXR agonist based on the particular patient, e.g., “a sufficient amount of the FXR agonist to treat a hepatitis B virus infection at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed, the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination with the specific agonist employed; and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. However, the daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per adult per day.” Andre et al. at page 51, lines 10-24.
Andre et al. does not explicitly teach the method according to claim 16, wherein the FXR agonist is administered twice a day (claim 20).
Pruzanski et al. is directed to pharmaceutical compositions comprising a combination of an FXR agonist and at least one additional therapeutic agent. See Pruzanski et al. at abstract. Pruzanski et al. teaches the pharmaceutical composition may be used to treat HBV. See Pruzanski et al. at page 20, lines 3-5. Pruzanski et al. also teaches embodiments where the FXR pharmaceutical composition can be administered twice daily, (claim 20) e.g., Pruzanski et al. discusses embodiments of its invention having prolonged action and teaches that immediate release forms of the invention may be administered three times a day, and that alternatively sustained release or immediate release forms of the invention may be administered twice daily to achieve the desired daily dosage. See Pruzanski et al. at pages 29-30, lines 26-11.
Additionally, it is reasonable to optimize the number doses per day according to the particularities of patients by use of reasonable medical judgments, leading to a wide range of possible doses for the patients. See Andre et al. at page 51, discussed above. The number of doses per day can clearly be a result effective parameter that a person having ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient, i.e., the dosage and dosing regimen, needed to achieve the desired results. The principle of law states from MPEP § 2144.05: "The normal desire of Application/Control Number: 18/265,380 Page 30 Art Unit: 1674 scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages," (see In re Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382). Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here 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 In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)).
It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to modify the method as taught by Andre et al. with the dosage frequency of Pruzanski et al. to administer the FXR agonist twice daily at least because Andre et al. teaches that optimization of dosages, amount of daily usage which dependent on a number of factor such as the patients age, weight, severity of disease, etc.in the treatment of HBV and Pruzanski teaches dosing the FXR agonist twice a day and the possibility of “prolonged action” of the therapeutic, which would be enhanced by dosing twice a day rather than once a day. The person of ordinary skill in the art would then be motivated to dose the FXR agonist twice a day because Pruzanski et al. suggests dosing twice a day may result in superior administration of the FXR agonist for treating HBV.
Furthermore, it is obvious to combine prior art elements according to known methods to yield predictable results. In this case, each element (e.g., the treatment of Andre et al. and the “twice a day” dosing of Pruzanski et al.) merely performs the same function as it does separately. A person of ordinary skill in the art would also have a reasonable expectation of success in treating HBV infection with the FXR inhibitor twice daily because Pruzanski et al. suggests that dosing the FXR agonist twice a day may help achieve “prolonged action” of the FXR agonist. It was therefore predictable that dosing the FXR agonist twice a day would result in an operable HBV infection treatment.
Pertinent Art
12. The prior art made of record and not relied upon is considered pertinent to Applicant’s disclosure:
Radreau et al. ("Reciprocal regulation of farnesoid X receptor α activity and hepatitis B virus replication in differentiated HepaRG cells and primary human hepatocytes." The FASEB Journal 30.9 (2016): 3146-3154); discloses evaluating the effects of FXR activation (e.g., using GW4064) on HBV replication using differentiated HepaRG cells and primary human hepatocytes (PHHs), e.g., the same models used by Applicant (Radreau et al. at abstract). Radreau et al. treats the models with 1 and 10 µM GW4064, the same as Applicant at instant FIGs. 3-5, and also with 0.1 and 0.01 µM GW4064 (i.e., 10-100x less than Applicant). Radreau et al. at FIGs. 1A, 2A.
Conclusion
13. No claim is allowed.
14. Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRANDON R SCHWECHTER whose telephone number is (571)272-1270. The examiner can normally be reached M-Th 7-5 EST.
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/BRANDON R SCHWECHTER/
Examiner, Art Unit 1674
/VANESSA L. FORD/ Supervisory Patent Examiner, Art Unit 1674