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
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or
under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. This application claims benefit of Foreign Application EPO 21382731.4 dated 08/03/2021. Based on the filing receipt, the effective filing date of this application is August 3, 2021 which is the filing date of Foreign Application EPO 21382731.4 from which the benefit of priority is claimed.
Information Disclosure Statement
The information disclosure statement (IDS) filed 02/01/2024 has been considered.
Status of Claims
Claims 1-15 are cancelled in amendments filed 01/30/2024.
Claims 16-31 are pending and examined herein.
Claim Objections
Claim 29 objected to because of the following informalities:
Claim 29 recites, “The treatment method according to claim 16, wherein the subject is one suffering from chronic liver disease,”. The claim should recite, “The treatment method according to claim 16, wherein the subject is one suffering from chronic liver disease[[,]].”. Appropriate correction is required.
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 16-31 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for measuring the gene expression of one or both of the markers E-cadherin (ECAD) and serine peptidase inhibitor Kazal type I (SPINK1) in serum, does not reasonably provide enablement for measuring ECAD and/or SPINK1 in all fluid samples. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
As set forth in In re Wands, 858 F .2d 731, 8 USPQ2d 1400 (Fed. Cir. 1988), enablement requires that the specification teach those in the art to make and use the invention without undue experimentation. Factors to be considered in determining whether a disclosure would require undue experimentation include 1) the nature of the invention, 2) the state of the prior art, 3) the predictability or lack thereof in the art, 4) the amount of direction or guidance present, 5) the presence or absence of working examples, 6) the quantity of experimentation necessary, 7) the relative skill of those in the art, and 8) the breadth of the claims.
The nature of the invention relates to measuring ECAD and SPINK1 in isolated fluid samples to identify portal hypertension. Claim 24 specifies the fluid test sample is selected from the group consisting of whole blood, plasma, serum, urine and saliva.
Regarding the breadth of the claims, the claims are broad because they encompass detecting the biomarkers in all fluid biological samples from a subject, including blood, bile, bone marrow aspirate, breast milk, cerebral spinal fluid, saliva, sputum, stool, swabs (oral, nasal, vaginal fluids), synovial fluid, and urine.
The amount of guidance regarding reduction to practice of urine and saliva is nonexistent in the applicant’s specification. The reduction to practice is limited to serum tests.
The state of the prior art lacks any disclosure of measuring ECAD and SPINK1 in isolated fluid samples to identify portal hypertension.
The unpredictability in the art is high. Gao (“Differences in blood and urine biomarker discovery”, published 2015) teaches, “there must be significant differences between blood and urine biomarker discovery” (see, p. 143, under “Opinion”, para. 1). The sample type cannot be substituted for one another with a reasonable expectation of success.
As is appreciated in the art, one skilled in the art would face an undue burden of examination in extrapolating the data presented regarding measuring ECAD and SPINK1 in fluid samples. The specification fails to enable the skilled artisan to employ measurement techniques for all fluid samples. In particular, the specification only provides guidance to measurement in serum.
In summary, the specification only reduced to practice the measurement of serum ECAD and/or SPINK1 to identify portal hypertension. There would be an undue experimentation to extrapolate data for the measurement of ECAD and/or SPINK1 in urine or saliva to identify portal hypertension.
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 17-18, 20, 22, 28, and 31 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 17-18, 20, and 22, the phrases “reference control value V1” and the reference control value “V2” renders the claims indefinite because it is unclear what the values are. The specification gives guidance on obtaining reference values on p. 7, but it is still unclear what the specific values are, therefore, the metes and bounds of the claims cannot be ascertained.
Regarding claim 28, the phrase "particularly" renders the claim indefinite because it is unclear whether the limitation following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 31, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
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.
Claim 16-18 and 20-31 rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon without significantly more.
Regarding claims 16-18 and 20-31, the claims recite a treatment method comprising measuring one or both of E-cadherin (ECAD) and serine peptidase inhibitor Kazal type I (SPINK1) to identify the subject as having portal hypertension (PH), therefore, the claims are directed at the relationship between ECAD/SPINK1 and portal hypertension. These judicial exceptions are not integrated into a practical application, such as constituting an improvement in the technological field, or including steps recited in addition to the judicial exception that integrates detection of the natural phenomena into a particular treatment/prophylaxis according to MPEP § 2106.04(d)(2). The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exceptions because the additional elements fail to provide either an inventive concept or impose meaningful limits upon the method such that the invention does not preempt every observance of the natural phenomenon itself.
Eligibility Step 1:
Claims 16-18 and 20-32 are directed to treatment methods comprising measuring ECAD/SPINK1 to identify portal hypertension. Methods are one of the eligible statutory categories for invention (STEP 1: YES). However, eligibility of the claims is not self-evident, and therefore analysis must proceed to Step 2.
Eligibility Step 2A, Prong One:
The natural relationships to which the claims are directed (i.e. the relation between levels of biomarkers ECAD/SPINK1 and PH) are laws of nature. Similar concepts have been held by the courts to constitute law of nature/ natural phenomena, as in the identification of a correlation between the presence of in a bodily sample (such as blood or plasma) and cardiovascular disease risk in Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1361, 123 USPQ2d 1081, 1087 (Fed. Cir. 2017). In Mayo, the Supreme Court found that a claim was directed to a natural law, where the claim required administering a drug and determining the levels of a metabolite following administration, where the level of metabolite was indicative of a need to increase or decrease the dosage of the drug. See Mayo Collaborative Services v. Prometheus Labs., Inc., 566 U.S. 66, 74 (2012).
The instant claims are similar to those in Mayo as they involve a "relation itself [which] exists in principle apart from any human action" (id. at 77), namely the relationship between the naturally occurring levels of biomarkers comprising ECAD and SPINK1 in a biological sample and the presence of portal hypertension. Therefore, the claims recite at least one judicial exception (STEP 2A, Prong One: YES).
The claims also recite the following limitations “wherein the subject having portal hypertension (PH) is a subject where the amount of the gene expression product of one or both of the markers E-cadherin (ECAD) and serine peptidase inhibitor Kazal type I (SPINK1) is above a reference control value V1” (claim 17), and “wherein the reference control value V1 is calculated by measuring the amount of the one or both markers in a group of samples from subjects with a portal pressure equal or lower than 5 mm Hg” (claim 18), “where the amount of the gene expression product of one or both of the markers E-cadherin (ECAD) and serine peptidase inhibitor Kazal type I (SPINK1) is between the reference control values V1 and V2, wherein V1 is calculated by measuring the amount of the one or both markers in a group of samples from subjects with a portal pressure equal or lower than 5 mm Hg, and V2 is calculated by measuring the amount of the one or both markers in a group of samples from subjects with a portal pressure equal or lower than 10 mm Hg and higher than 5 mm Hg” (claim 20), “wherein the subject having clinically significant portal hypertension (CSPH) is a subject where the amount of the gene expression product of one or both of the markers E-cadherin (ECAD) and serine peptidase inhibitor Kazal type I (SPINK1) is equal or above a reference control value V2, wherein V2 is calculated by measuring the amount of the one or both markers in a group of samples from subjects with a portal pressure equal or lower than 10 mmHg and higher than 5 mmHg” (claim 22), “wherein the amount of both the E-cadherin (ECAD) and the serine peptidase inhibitor Kazal type I (SPINK1) markers is determined”, “wherein the subject is one suffering from chronic liver disease” (claim 29), and “wherein the chronic liver disease is cirrhosis” (claim 30). These claim limitations are all directed at the natural relationship between ECAD/SPINK1 and portal hypertension. The claims are only further specifying the features of the natural relationship.
Eligibility Step 2A, Prong Two:
According to Step 2A, Prong Two, set forth in MPEP 2106.04 II A (2), the claims are next evaluated with respect to whether the judicial exception is integrated into a practical application. This analysis turns to the additional steps/elements recited within the claims. In independent claim 16, the additional steps are “administering a treatment to the patient having portal hypertension (PH), wherein the treatment is selected from the group consisting of beta-blockers, lactulose, enemas, diuretics, antibiotics, surgery, statins, dialysis, and combinations thereof”. Dependent claim 21 recites, “The treatment method according to claim 16, wherein the subject is identified as having clinically significant portal hypertension (CSPH) and wherein the treatment administered to the subject having clinically significant portal hypertension (CSPH) is selected from the group consisting of statins, beta-blockers, surgery, and combinations thereof”. Dependent claims 24-28 provide additional limitations on biomarker type, sample type, and the measurement assay. Dependent claim 31 adds another measurement and further correlation factors.
Regarding the additional steps cited in claims 16 and 21, the treatments such as “surgery” and “enemas” are recited at a high level of generality and are not tied, for example to any particular surgical procedure or enema treatment. The treatment or prophylaxis limitation must be “particular,” i.e., specifically identified so that it does not encompass all applications of the judicial exception(s). See MPEP 2106.04(d)(2).
Regarding claims 24-28, obtaining a biological sample and measuring biomarker levels are insufficient to integrate the judicial exception 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). Furthermore, the steps of measuring biomarkers are recited at a high level of generality and are not tied, for example, to any particular machine or apparatus.
There are no additional elements that reflect an actual improvement within the technical field. For example, there are no additional elements that apply the natural correlation/phenomena judicial exception to a particular treatment or which utilize a particular machine; there are no additional elements that effect a transformation; and, there are no additional elements that apply the judicial exception in some other meaningful way beyond generally linking it to a field, namely, portal hypertension diagnosis. In this way the claims, as drafted, do not integrate the judicial exception into a practical application that would overcome monopolizing the exception. (STEP 2A, Prong Two: NO).
Eligibility Step 2B:
Lastly, the additional elements of claims 24-28 are well-understood, routine, conventional in nature.
Regarding the steps specific to obtaining a sample and measuring serum biomarkers, specifically proteins, using an antibody in an ELISA kit, the following prior art teaches that it was established in the field of technical expertise that such steps are well-understood, routine, and conventional. Chen (“Hepatic lipocalin 2 promotes liver fibrosis and portal hypertension”, published 2020, cited in IDS filed 02/01/2024) teaches serum measurements with antibodies from an ELISA kit of hepatic lipocalin 2 to identify portal hypertension (see, e.g., p. 1, under abstract, and p. 10, under “Serum LCN2 and ET1 determination”). Liu (“Increased expression of urotensin II and GPR14 in patient with cirrhosis and portal hypertension”, published 2010, cited in IDS filed 02/01/2024) teaches the expression of the receptor for urotensin II, UT, is enhanced in patient with portal hypertension (see, e.g., p. 845, under “Abstract.”).
Therefore, the steps/elements recited in addition to the judicial exception were all well understood, routine, conventional activities in the field of portal hypertension detection prior to filing the application at hand (STEP 2B: NO).
The claimed steps/elements recited in addition to the judicial exception, alone or in combination, do not make an inventive contribution over the methods that were known in the art prior to filing, and they amount to mere observation of the natural phenomenon itself, by any means known, with the words “apply it” in order to append it to the field of portal hypertension detection.
For all of these reasons, the claimed subject matter is ineligible under 35 U.S.C. 101 because the claims are directed to a natural phenomenon judicial exception without significantly more.
However, it is noted that claim 19 does integrate the judicial exception into a practical application by tying the identification of a subject having non-clinically significant portal hypertension to the treatment with a particular treatment, beta-blockers.
Conclusion
Claims 16-31 are free of the prior art. However, claims 16-18 and 20-31 are rejected on the grounds of 35 U.S.C. 101 and claims 16-31 are rejected on the grounds of 35 U.S.C. 112(a).
The prior art of record does not teach or make obvious independent claim 16 recites, “A treatment method comprising:
(a) measuring the amount of the gene expression product of one or both of the markers E- cadherin (ECAD) and serine peptidase inhibitor Kazal type I (SPINK1) in an isolated fluid sample from a subject to identify the subject as having portal hypertension (PH), and
(b) administering a treatment to the patient having portal hypertension (PH), wherein the treatment is selected from the group consisting of beta-blockers, lactulose, enemas, diuretics, antibiotics, surgery, statins, dialysis, and combinations thereof”.
The closest art of record is Craig (“Dysregulation of cadherins in the intercalated disc of the spontaneously hypertensive stroke-prone rat”, published 2010-06, cited in IDS filed 02/01/2024). Craig teaches measuring the amount of the gene expression product of E-cadherin in the hearts of stroke-prone spontaneously hypertensive (SHRSP) rats (see, e.g., p. 1121, under “ABSTRACT”). However, Craig fails to teach identifying the subject as having portal hypertension and administering a treatment. SHRSP rats are a genetic model of cardiac hypertrophy (see, e.g., p. 1121, under “ABSTRACT”). Therefore, an artisan would not have expected based on the disclosure of Craig that E-cadherin is a biomarker for portal hypertension.
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/MICHAEL CAMERON SVEIVEN/ Examiner, Art Unit 1678
/GREGORY S EMCH/ Supervisory Patent Examiner, Art Unit 1678
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