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 .
DETAILED ACTION
Responsive to communication entered 01/28/2026.
Note: the examiner of the instant application has changed.
Priority
This application, filed 08/24/2020, Pub. No. US 2020/0393473 A1, published 12/17/2020, is a national stage entry of PCT/US19/18038, filed 02/14/2019, Pub. No. WO 2019/164749 A1, published 08/29/2019, which claims priority to US provisional application 62/635,273, filed 02/26/2018.
Oath/Declaration
The two declarations under 37 C.F.R. 1.132 filed 01/28/2026 have been considered by the examiner.
Status of Claims
Claims 1-55 have been cancelled, as set forth in Applicant’s Amendment filed 01/28/2026. Claims 56-75 are currently pending and examined herein.
Withdrawn Objections/Rejections
Any objection or rejection not reiterated herein has been withdrawn.
The rejections of claims 34, 36, 39-40, and 54-55 under 35 U.S.C. 101 are moot in view of Applicant’s cancellation of the claims.
The objection to claims 34, 36, 39-40, and 54-55 under 35 U.S.C. 103 are moot withdrawn in view of Applicant’s amendment of the claim.
New rejections, necessitated by amendments, are discussed below.
Claim Objections
Claim 68 is objected to because of the following informalities: the claim recites “wherein detection of EZE-Gluc, EZE, or combination comprises LS-MS/MS”. Appropriate correction is required.
For the purpose of applying prior art, claim 68 will be interpreted to be directed at detection using LC-MS/MS, as in claims 73 and 75.
Claim Rejections - 35 USC § 112
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 60, 73, and 75 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.
Claims 60, 73, and 75 recite administering a “1 mg” dose of ezetimibe (EZE). However, the specification does not properly describe using the claimed methods with a 1 mg dose of EZE. The Applicant only gives the administration of a 1 mg dose of EZE as one of the many examples of doses in para. [0039] of the Applicant’s specification. There is no other disclosure of a 1 mg dose of EZE. Furthermore, there is no reduction to practice of providing a 1 mg dose of EZE to a human subject. Example 2 of the Applicant’s specification, found on para. [0056]-[0060], merely gives a prophetic example of providing a 10 mg dose of EZE to a human subject.
Regarding predictability in the art, Cherrington, US 2016/0209435, published 07/21/2016 (PTO-892 mailed 05/03/2024), teaches:
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The disclosure of Cherrington gives evidence that a maximal dose of a drug is desired to facilitate the analysis of metabolite formation. It is not clear that a 1 mg dose of ezetimibe would be a high enough dose to analyze metabolite formation and the Applicant’s specification does not provide evidence that a 1 mg dose of ezetimibe is sufficient.
For these reasons, the specification does not demonstrate possession of the claimed invention of Claims 60, 73, and 75.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 56-59, 61-72, and 74 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more.
This rejection is modified from the previous Office Action.
The claims, as recited in independent Claims 56, 72, and 74, are drawn to:
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Claim interpretation: The broadest reasonable interpretations of Claims 56, 72, and 74 are methods for assessing the ezetimibe (EZE) and/or ezetimibe-glucuronide (EZE-Gluc) concentrations in fluid samples from a human subject as a marker(s) of non-alcoholic steatohepatitis (NASH).
Step 1: This part of the eligibility analysis evaluates whether the claim falls within any statutory category. MPEP § 2106.03. The claim recites at least one step or act, including “detecting the amount of ezetimibe-glucuronide (EZE-Gluc), ezetimibe (EZE), or a combination thereof” and “diagnosing the subject with NASH” Thus, the claim is to a process, which is one of the statutory categories of invention (Step 1: YES).
Step 2A Prong One: This part of the eligibility analysis evaluates whether the claim recites a judicial exception. As explained in MPEP § 2106.04(II), a claim “recites” a judicial exception when the judicial exception is “set forth” or “described” in the claim. While the terms "set forth" and "described" are thus both equated with "recite", their different language is intended to indicate that there are two ways in which an exception can be recited in a claim. For instance, the claims in Diehr, 450 U.S. at 178 n. 2, 179 n.5, 191-92, 209 USPQ at 4-5 (1981), clearly stated a mathematical equation in the repetitively calculating step, and the claims in Mayo, 566 U.S. 66, 75-77, 101 USPQ2d 1961, 1967-68 (2012), clearly stated laws of nature in the wherein clause, such that the claims “set forth” an identifiable judicial exception. Alternatively, the claims in Alice Corp., 573 U.S. at 218, 110 USPQ2d at 1982, described the concept of intermediated settlement without ever explicitly using the words “intermediated” or “settlement.” Here, Claims 56, 72, and 74 describe a law of nature—namely, a relationship between a chemical, ezetimibe (EZE), and/or its metabolite ezetimibe-glucuronide (EZE-Gluc) in a fluid sample from a human subject and the likelihood that the subject has non-alcoholic steatohepatitis (NASH). The relationship between ezetimibe (EZE), and/or its metabolite ezetimibe-glucuronide (EZE-Gluc) in a fluid sample from a human subject and the likelihood that the subject has NASH is a law of nature because the relationship exists outside of any human action. In addition, Claims 56, 72, and 74 recite “diagnosing the subject with NASH.” The “diagnosing” can be practically performed in the human mind, and thus falls into the “mental process” groupings of abstract ideas.
Accordingly, Claims 56, 72, and 74 recite a judicial exception (an abstract idea that falls within the mental process grouping and a law of nature).
Step 2A Prong Two: This part of the eligibility analysis evaluates whether the claims as a whole integrate the recited judicial exception into a practical application of the exception. This evaluation is performed by (a) identifying whether there are any additional elements recited in the claim beyond the judicial exception, and (b) evaluating those additional elements individually and in combination to determine whether the claim as a whole integrates the exception into a practical application.
Besides the abstract idea/law of nature, the claim recites the additional element of “detecting” the amount of ezetimibe-glucuronide (EZE-Gluc), ezetimibe (EZE), or a combination thereof and “a fluid sample obtained from a human subject after the subject has been administered EZE”. However, elements of administering/obtaining/detecting are insufficient to integrate the judicial exception(s) into a practical application because the purpose is merely to obtain data. This does not go beyond insignificant presolution activity, i.e., a mere data gathering step necessary to use the correlation, similar to the fact pattern in In re Grams, 888 F.2d 835 (Fed. Cir. 1989) and Ariosa Diagnostics, Inc. v. Sequenom, Inc. (Fed. Cir. 2015). Such steps that merely “add insignificant extra-solution activity to the judicial exception” are insufficient to integrate the exception into a practical application (MPEP 2106.05(g)). Data gathering steps typically constitute such insignificant extra-solution activity. See Mayo (concluding that additional element of measuring metabolites of a drug administered to a patient was extra-solution activity); OIP Techs., Inc. v. Amazon.com, Inc., 788 F.3d 1359, 1363 (Fed. Cir. 2015) (holding that mere data gathering is insufficient to confer patent eligibility).
The further defined additional elements recited in the claims, do not represent an improvement to a technical field, as such techniques were previously known (see discussion below), and, accordingly, do not apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception.
Accordingly, these limitations do not integrate the recited judicial exception into a practical application and the claims are therefore directed to the judicial exception (Step 2A: YES).
Step 2B: This part of the eligibility analysis evaluates whether the claim as a whole amount to significantly more than the recited exception, i.e., whether any additional element, or combination of additional elements, adds an inventive concept to the claim. See MPEP § 2106.05.
Regarding Claims 56, 72, and 74 measuring EZE and/or EZE-Gluc concentration was well-known, understood and routine in the prior art. For example, Oswald et al., “A LC-MS/MS method to quantify the novel cholesterol lowering drug ezetimibe in human serum, urine and feces in healthy subjects genotyped for SLCO1B1,” J. Chromatogr. B, 2006 vol. 830, pp. 143–150 (PTO-892 mailed 05/03/2024), teach:
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Emphasis added.
Hardwick et al., “Molecular mechanism of altered ezetimibe disposition in nonalcoholic steatohepatitis,” Drug Metab. Dispos., 2012, vol. 40, No 3, pp. 450-460, Epub 2011 Nov 23 (IDS submitted 04/27/2023), at pages 452-453, teach:
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Claims 56, 72, and 74 are not eligible.
Regarding Claims 57-59, 61, 64, and 66, recitations “wherein the subject was administered a subtherapeutic dose of EZE” and “the fluid sample is taken between 1 hour and 6 hours after the EZE is administered” are simply appending well-understood, routine, conventional activities previously known to the industry, because one of skill in the art would have known that EZE is clinically administered as a 10-mg oral dose:
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Note: Claims 58-59 disclose that 10 mg is a subtherapeutic dose. Moreover, as evidenced by Hardwick et al., it is a common practice to obtain the samples within 10-120 minutes after EZE administration. See Figures 3-5. Claims 57-59, 61, 64, and 66 are not eligible.
Regarding Claims 62-63, 65, 72, and 74, recitations of the sample as “urine” or “plasma” are simply appending well-understood, routine, conventional activities previously known to the industry as evidenced by Hardwick et al., “Molecular mechanism of altered ezetimibe disposition in nonalcoholic steatohepatitis,” Drug Metab. Dispos., 2012, vol. 40, No 3, pp. 450-460, Epub 2011 Nov 23 (IDS submitted 04/27/2023), at pages 453-455, specifically under “Fig. 3.” and “Fig. 5.”, which teaches measuring EZE in urine and plasma. Claims 62-63, 65, 72, and 74 are not eligible.
Regarding Claims 67-68, 72, and 74, recitations “wherein detection of EZE-Gluc, EZE or comibnations comprises liquid chromatography (LC), mass spectroscopy (MS), an immune assay, or a combination thereof” and “wherein detection of EZE-Gluc, EZE, or combination comprises LS-MS/MS [sic]” are simply appending well-understood, routine, conventional activities previously known to the industry as evidenced by Hardwick et al., “Molecular mechanism of altered ezetimibe disposition in nonalcoholic steatohepatitis,” Drug Metab. Dispos., 2012, vol. 40, No 3, pp. 450-460, Epub 2011 Nov 23 (IDS submitted 04/27/2023), at page 453:
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Claims 67-68, 72, and 74 are not eligible.
Regarding Claim 69, recitations “wherein the control is a reference level formed from an aggregate population of asymptomatic individuals without NASH” are simply appending well-understood, routine, conventional activities previously known to the industry as evidenced by Hardwick et al., “Molecular mechanism of altered ezetimibe disposition in nonalcoholic steatohepatitis,” Drug Metab. Dispos., 2012, vol. 40, No 3, pp. 450-460, Epub 2011 Nov 23 (IDS submitted 04/27/2023), at pages 453-455, specifically under “Fig. 3.” and “Fig. 5.”. Claims 69 is not eligible.
Regarding Claims 70 and 71, recitations “further comprising prescribing a therapy to the subject for NASH when the subject is diagnosed with NASH” and “wherein the therapy comprises dietary changes, exercise regimens, lifestyle changes, surgical interventions, or use of medications”, respectively, fail to meaningfully limit the claim because the therapy is not necessarily required. Furthermore, these recitations do not provide any information as to how the patient is to be treated, or what the treatment is, but instead covers any possible treatment that a doctor decides to administer to the patient. In fact, these limitations are recited at such a high level of generality that it does not even require a doctor to take the determined EZE and/or EZE-Gluc concentration into account when deciding which treatment to administer, making the limitation's inclusion in these claims at best nominal. Like the claims in Mayo Collaborative Servs. v. Prometheus Labs., Inc., 566 U.S. 66, 78 (2012), Claims 70 and 71 here tell the relevant audience (doctors) about the law of nature and at most adds a suggestion that the doctors take this law into account when treating their patients. These limitations thus fail to meaningfully limit the claims because they do not require any particular application of the determined EZE and/or EZE-Gluc concentration for the patient and is at best the equivalent of merely adding the words "apply it” to the judicial exception. Accordingly, these limitations do not integrate the recited judicial exception into a practical application and the claims are therefore directed to the judicial exception. See MPEP 2106.05(f), which provides a detailed explanation and examples of how courts have evaluated the "mere instructions to apply an exception" consideration.
Claims 70 and 71 are not eligible.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
Claims 56-59, 61-72, and 74 are rejected under 35 U.S.C. 103 as obvious
over Cherrington, US 2016/0209435, published 07/21/2016 (PTO-892 mailed 05/03/2024), in view of Hardwick et al., “Molecular mechanism of altered ezetimibe disposition in nonalcoholic steatohepatitis,” Drug Metab. Dispos., 2012, vol. 40, No 3, pp. 450-460, Epub 2011 Nov 23 (IDS submitted 04/27/2023).
This rejection is modified from the previous Office Action.
Regarding Claims 56, 61-66, 72, and 74, Cherrington, throughout the publication, and, for example, in the claims teaches:
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In paragraph [0047], Cherrington teaches:
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Emphasis added.
In paragraphs [0051]-[0052], Cherrington teaches:
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In paragraph [0084], Cherrington teaches:
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One of skill in the art would have understood that “ezeitimibe,” taught by Cherrington, is meant to be “ezetimibe,” because there appears to be no such therapeutic drug as “ezeitimibe.” Moreover, US provisional application 61/194,835, which incorporated by reference into Cherrington’s disclosure, provides the correct spelling of “ezetimibe”:
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See page 38; Emphasis added.
The Examiner further notes that the disclosure of US provisional application 61/194,835, which has been filed on 10/01/2008, comprises a draft of Lickteig et al., “Efflux transporter expression and acetaminophen metabolite excretion are altered in rodent models of nonalcoholic fatty liver disease,” Drug Metab. Dispos., 2007, vol. 35, No 10, pp. 1970-1978, Epub 2007 Jul 19 (PTO-892 mailed 05/03/2024), wherein the corresponding paragraph reads as follows:
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Emphasis added.
Regarding Claims 70 and 71, Cherrington teaches:
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Emphasis added.
As such, Cherrington teaches all steps of the instantly claimed method but does not specifically teach the use of the ezetimibe (EZE) and/or ezetimibe-glucuronide (EZE-Gluc) concentrations in urine samples or plasma samples from a human subject as a marker(s) of non-alcoholic steatohepatitis (NASH).
Hardwick et al., throughout the publication, and, for example, in Abstract, teach:
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Hardwick et al. teach orally and intravenously dosing rodent model with a subtherapeutic EZE dose of approximately 2 mg to discern the hepatic contribution to EZE disposition in NASH (i.e., administering EZE), as in claims 56-59, 72, and 74 (page 451, col. 2, lines 3-4, and p. 452, col. 1, para. 1-2). The teaching includes, blood and urine samples were collected following EZE administration, as in claims 62-63, 65, 72, and 74. Furthermore, the teaching includes, that NASH may cause a shift in the disposition profile of clinically relevant drugs is seen in the urinary excretion of total EZE and EZE (i.e. sample obtained following administration of EZE being used to diagnose NASH), as in claims 56, 72, and 74 (Page 452, col. 2, para 1 and page 458, col. 2, para 2).
Hardwick et al. teach determining an amount of EZE and/or ezetimibe-glucuronide (EZE-Gluc) in the urine sample obtained from the subject following LC-MS/MS detection of total EZE, EZE and EZE-Gluc, as in claims 67-68, 72, and 74 (page 452, col. 2, para 1, lines 2-3 and page 453, col. 1, para 1 and 2). Furthermore, Fig 3 shows comparison of EZE and EZE-Gluc to a control comprising an aggregate population of asymptomatic individuals without NASH beginning 2 mins after dose until 120 mins, as in claims 56, 69, and 72. Fig. 5 shows EZE and EZE-Gluc in urine 120 mins following administration of drug in comparison to control comprising an aggregate population of asymptomatic individuals without NASH, wherein the sample is elevated relative to the control, as in claims 56, 69, and 74.
It would have been prima facie obvious, before the effective filing date of the claimed invention, for one of ordinary skill in the art to have made and used ezetimibe-glucuronide (EZE-Gluc), taught by Hardwick et al., as a substituting equivalent of acetaminophen-glucoronide (APAP-glucoronide) in the method, taught by Cherrington, because both APAP-glucoronide and ezetimibe-glucoronide (EZE-Gluc) are the biomarkers of a hepatic disorder, such as NASH, as taught by Cherrington and Hardwick et al., respectively.
Response to Arguments
Applicant's arguments filed 01/28/2026 have been fully considered but they are not persuasive.
Rejection Under 35 USC § 103
At pages 8-10 of Remarks, Applicant argues that:
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Underline emphasis added.
The Office respectfully disagrees for the following reasons.
First, in regards to toxicity, Hardwick et al on pages 457-458 teaches:
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Hardwick does not teach away from using EZE-GLUC for diagnosing NASH. While Hardwick mentions that “In general, elevated plasma efflux of a drug” could affect toxicity, they continue by stating “increased efflux of EZE-GLUC into sinusoidal blood […] could possibly play a role in selection of the most appropriate therapeutic option for patients with NASH”. A artisan of ordinary skill in the art would have seen that the change in disposition for subjects with NASH would be a valuable diagnostic marker that could inform therapeutic options, as evidenced by the disclosure of Hardwick.
Furthermore, the broadest reasonable interpretation of the instant invention includes the use of ezetimibe for diagnostic purposes in cases where the stratification of a patient is necessary. For example, Cherrington (cited above) teaches in paragraph [0052]:
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The disclosure by Cherrington provides evidence of a market need for a non-invasive method of diagnosing NASH. The current method for diagnosing NASH depends on liver biopsy. A health practitioner would have understood a one-time dose of ezetimibe to be a preferable option to liver biopsy, despite the potential toxicity concerns relating to ezetimibe. In addition, in paragraph [0041], Cherrington teaches:
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Emphasis added.
Cherrington discloses that administering acetaminophen has toxicity risks but that those risks can be minimized by administering a dose below a threshold. An artisan would have understood that the same logic could be applied to doses of ezetimibe.
At pages 10-11 of Remarks, Applicant argues that:
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Underline emphasis added.
The Office respectfully disagrees. EZE being a more sensitive marker for NASH than ADAP is not unexpected. In Hardwick, “Fig. 3” on page 453 shows total EZE concentrations in the plasma of diet-induced NASH subjects after 2 hours is many multiples the concentration of the healthy control subjects:
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Conversly, “Figure 4” on sheet 4 of 6 of Cherrington shows the concentration of APAP and its major metabolites in plasma after 4 hours:
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The difference in total acetaminophen concentration in NASH subjects compared to the control subjects is only 2-fold, substantially lower than the total EZE concentration difference. Therefore, it the use of EZE as a diagnostic marker for NASH is not unexpectedly better.
At page 11 of Remarks, Applicant argues that:
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Emphasis added.
However, the Office respectfully disagrees. While Cherrington teaches that a 1000 mg of APAP is preferred to balance the risk of toxicity with facilitating analysis of metabolite formation, there is no evidence provided that 1 mg of EZE is unexpectedly less toxic to patients than 1000 mg of APAP. Therefore, the use of a lower dose of EZE does necessarily mean that EZE is an unexpectedly better diagnostic marker than APAP.
At page 12, the Applicant argues:
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The Office respectfully disagrees. While the Second Cherrington Decleration shows an impresively high AUROC of 0.99, there is no reason to believe this is a surprising result given that in Hardwick, “Fig. 3” on page 453 shows total EZE concentrations in the plasma of diet-induced NASH subjects after 2 hours is many multiples the concentration of the healthy control subjects. Therefore, the Office asserts that EZE is not unexpectedly better than APAP as a diagnostic marker.
Rejection Under 35 USC § 101
At pages 12-14 the Applicant argues:
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While the argument regarding subject matter eligibility is acknowledged, it is not persuasive for the following reasons. Section 2106 of the MPEP clearly enumerates the criteria for patent subject matter eligibility. The rejection of claims 56-59, 61-72, and 74 on the grounds of 35 U.S.C. 101 above is consistent with the guidance of MPEP 2106. Furthermore, the Office agrees that examiners and panels should not evaluate claims at a high level of generality without adequate explanation of why an invention is directed at a judicial exception and why the additional elements do not add significantly more. Each application must be examined on merit and the individual fact-pattern of the case. However, the rejection of the claims above on the grounds of 35 U.S.C. 101 provides adequate explanation for why the claimed invention is not eligible.
At pages 14-15 the Applicant argues:
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Emphasis added.
The Office respectfully disagrees. As discussed above, Cherrington discloses a method that comprises administering a potentially toxic drug (acetaminophen) to a patient for diagnostic purposes. Also discussed above, Hardwick provided evidence that EZE disposition is different in diet-induced NASH subjects as compared to healthy control subjects and stated that the change in disposition could influence selection of therapeutics for NASH patients. The response above provides the evidence that the substitution of EZE for APAP in the method of Cherrington is obvious, indicating that the instantly claimed method is not a significant improvement over the field. Applicant’s argument that “the instantly claimed method is a dramatic improvement thereof” is not sustainable under Ariosa Diagnostics, Inc. v. Sequenom, 788 F.3d 1371, 1373, 115 USPQ2d 1152, 1153 (Fed. Cir. 2015). In Ariosa Diagnostics, the court has identified the existence of cell-free fetal DNA (cffDNA) in maternal blood that solves a very practical problem accessing fetal DNA without creating a major health risk for the unborn child as an example of laws of nature or natural phenomena. See also MPEP 2106.04(b). For these reasons, the 35 U.S.C. 101 rejection has been upheld.
Conclusion
No claims are allowed. While claims 60, 73, and 75 are free of the prior art due to the administration of 1 mg dose of ezetimibe not being anticipated or rendered obvious by the prior art, the claims are nevertheless rejected on the grounds of 35 U.S.C. 112(a).
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/MICHAEL CAMERON SVEIVEN/Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678