DETAILED ACTION
The examiner of your application in the USPTO has changed. To aid in correlating any papers for this application, all further correspondence regarding this application should be directed to Fernando Ivich, Art Unit 1678.
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 .
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.
Withdrawn Objections/Rejections
The objection to the specification is withdrawn in response to the Remarks filed 6/20/2025 and the Application Data sheet filed 6/20/2025.
The objection of claim 1 is withdrawn in response to the amendments.
The rejection of the claims under 112b are withdrawn in response to the amendments. However, new grounds of rejection are set forth below.
The rejection of the claims under 101 are withdrawn in response to the amendments. However, new grounds of rejection are set forth below.
The rejection of the claims under 103 are withdrawn in response to the amendments. However, new grounds of rejection are set forth below.
Priority
Acknowledgment is made of the present application as a proper National Stage (371) entry of PCT Application No. PCT/US19/45092, filed 08/05/2019, which claims benefit under 35 U.S.C. 119(e) to provisional application No. 62/714,161, filed 8/3/2018 as per the Application Data sheet filed 6/20/2025.
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. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 62/714,161, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. Claims 10-20 contain subject matter which is not disclosed in the provisional application and therefore receive no priority benefit. Specifically, claim 10 recites “e. determining the presence of severe liver disease in the subject based on a cumulative assessment value of 8 or greater; and f. administering to the subject a treatment”; claim 14 recites “e. determining the presence of moderate liver disease in the subject based on a cumulative assessment value of 4-7; and f. administering to the subject a treatment”; and claim 17 recites “e. determining the presence of a least severe level of liver disease in the subject based on a cumulative assessment value of 2-3; and f. administering to the subject a treatment”, which are not disclosed in the provisional application No. 62/714,161. Similarly, dependent claims 11-13, 15-16 and 18-20 further limit the treatment step, which is not disclosed in the provisional application No. 62/714,161.
Claims 10-20 have an effective filing date of 8/5/2019, which is the filing date of the PCT/US19/45092 application.
Status of the Claims
Claims 10-20 are pending; claims 1-9 are canceled; claims 10-20 are newly recited. Claims 10-20 are examined below.
New Objections
Claim Objections
Claims 13, 16 and 20 are objected to because of the following informalities: In claims 13, 16 and 20 line 2, "pioglitizaone" appears to be a typographical error, namely it is suggested that "pioglitizaone" read as "pioglitazone". Appropriate correction is required.
New Rejection
Claim Rejections - 35 USC § 112
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 10-20 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.
Independent claims 10, 14 and 17 recite “c. assigning a score to each of the seven protein activities or levels as follows: i. a protein C activity >65% is assigned a score of 0, a protein C activity of 35-65% is assigned a score of 1, and a protein C activity <35% is assigned a score of 2; ii. a factor V activity >80% is assigned a score of 0, a factor V activity of 55-80% is assigned a score of 1, and a factor V activity <55% is assigned a score of 2; iii. a factor VIII activity < 140% is assigned a score of 0, a factor VIII activity of 140-200% is assigned a score of 1, and a factor VIII activity >200% is assigned a score of 2; iv. a protein S activity >50% is assigned a score of 0, and a protein S activity <50% is assigned a score of 2; v. a D-dimer level <0.5 ng/ml is assigned a score of 0, a D-dimer level of 0.5-1 ng/ml is assigned a score of 1, and a D-dimer level > 1 ng/ml is assigned a score of 2; vi. a sP-selectin level > 100 pg/mL is assigned a score of 0, a sP-selectin level of 50-100 pg/mL is assigned a score of 1, and a sP-selectin level <50 pg/mL is assigned a score of 2; and vii. an asTF level <0.3 pg/mL is assigned a score of 0, an asTF level of 0.3-0.5 pg/mL is assigned a score of 1, and an asTF level >0.5 pg/mL is assigned a score of 2”.
However, step c is not clear. Specifically, it is not clear how the activities or levels of some of the proteins are percentages given that a percentage does not define an activity or level of a protein. Indeed, a percentage implies a comparison to a whole or control, but no control or reference protein activity or level is recited in the claims. The specification suggests that a comparison to a control is required (“All CLD patients (n=42) were previously assigned a CP score; healthy controls (n=30) were age and sex matched” para. 56). Because of this, a person having ordinary skill in the art would not recognize the metes and bounds of the claim.
Furthermore, step e. is not clear. Specifically, it is not clear what is meant by “determining the presence of severe liver disease in the subject based on a cumulative assessment value of 8 or greater” (claim 10), “determining the presence of moderate liver disease in the subject based on a cumulative assessment value of 4-7” (claim 14) and “determining the presence of a least severe level of liver disease in the subject based on a cumulative assessment value of 2-3”. More specifically, the term “based on” is vague. It is not clear whether the recited cumulative assessment values correspond to the recited level of liver disease, or how these values are related to the liver disease level. A person having ordinary skill in the art would not recognize the metes and bounds of the claim.
Claims 11-13, 15-16 and 18-20 are included in this rejection because they depend from rejected claims 10, 14 and 17, respectively, but fail to clarify the scope of patent protection sought.
Maintained Rejections
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 10-12, 14-15 and 17-19 are rejected under 35 U.S.C. 101 because the claimed invention is directed to at least one judicial exception without significantly more.
The U.S. Patent and Trademark Office recently revised the MPEP with regard to § 101 (see the MPEP at 2106). Regarding the MPEP at 2106, in determining what concept the claim is “directed to,” we first look to whether the claim recites:
(1) any judicial exceptions, including certain groupings of abstract ideas (i.e., mathematical concepts, certain methods of organizing human activity such as a fundamental economic practice, or mental processes); and
(2) additional elements that integrate the judicial exception into a practical application (see MPEP § 2106.05(a)-(c), (e)-(h)).
Only if a claim (1) recites a judicial exception and (2) does not integrate that exception into a practical application, do we then look to whether the claim contains an “‘inventive concept’ sufficient to ‘transform’” the claimed judicial exception into a patent-eligible application of the judicial exception. Alice, 573 U.S. at 221 (quoting Mayo, 566 U.S. at 82). In so doing, we thus consider whether the claim:
(3) adds a specific limitation beyond the judicial exception that is not “well-understood, routine, conventional” in the field (see MPEP § 2106.05(d)); or
(4) simply appends well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception.
See MPEP 2106.
ELIGIBILITY STEP 2A: WHETHER A CLAIM IS DIRECTED TO A JUDICIAL EXCEPTION
Step 2A, Prong 1
The claims recite “A method for identifying severe liver disease” (claim 10), “ A method for identifying moderate liver disease” (claim 14) or “A method for identifying a least severe level of liver disease” (claim 17) “in a subject and treating the subject, the method comprising: a. obtaining a blood or plasma sample from the subject; b. measuring by using assays the activities or levels of the following seven proteins from the sample: protein C, factor V, factor VIII, protein S, D-dimer, sP-selectin, and alternatively spliced Tissue Factor (asTF); c. assigning a score to each of the seven protein activities or levels as follows: i. a protein C activity >65% is assigned a score of 0, a protein C activity of 35-65% is assigned a score of 1, and a protein C activity <35% is assigned a score of 2; ii. a factor V activity >80% is assigned a score of 0, a factor V activity of 55-80% is assigned a score of 1, and a factor V activity <55% is assigned a score of 2; iii. a factor VIII activity < 140% is assigned a score of 0, a factor VIII activity of 140-200% is assigned a score of 1, and a factor VIII activity >200% is assigned a score of 2; iv. a protein S activity >50% is assigned a score of 0, and a protein S activity <50% is assigned a score of 2; v. a D-dimer level <0.5 ng/ml is assigned a score of 0, a D-dimer level of 0.5-1 ng/ml is assigned a score of 1, and a D-dimer level > 1 ng/ml is assigned a score of 2; vi. a sP-selectin level > 100 pg/mL is assigned a score of 0, a sP-selectin level of 50-100 pg/mL is assigned a score of 1, and a sP-selectin level <50 pg/mL is assigned a score of 2; and vii. an asTF level <0.3 pg/mL is assigned a score of 0, an asTF level of 0.3-0.5 pg/mL is assigned a score of 1, and an asTF level >0.5 pg/mL is assigned a score of 2; d. summating the assigned scores of the seven proteins to obtain a cumulative assessment value” and “e. determining the presence of severe liver disease in the subject based on a cumulative assessment value of 8 or greater” (claim 10), “e. determining the presence of moderate liver disease in the subject based on a cumulative assessment value of 4-7” (claim 14) or “ e. determining the presence of a least severe level of liver disease in the subject based on a cumulative assessment value of 2-3”.
The natural relationship to which the claims are directed (i.e., the relation between protein C, factor V, factor VIII, protein S, D-dimer, sP-selectin, and asTF activities or levels and liver disease) is a law 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 myeloperoxidase 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 activities or levels of protein C, factor V, factor VIII, protein S, D-dimer, sP-selectin, and asTF in blood or plasma and the presence of liver injury.
The correlation between protein C, factor V, factor VIII, protein S, D-dimer, sP-selectin, and asTF activities or levels and disease is a judicial exception as it exists in principle apart from any human action; the correlation itself therefore cannot form the basis for eligibility. Similarly, it is a naturally occurring phenomenon that protein C, factor V, factor VIII, protein S, D-dimer, sP-selectin, and asTF activities or levels are elevated to different extents in liver disease vs. in disorders not affecting the liver.
Additionally, the claims also recite steps of “assigning a score …” (see step c.), “summating the assigned scores…” (see step d.) and “determining the presence of moderate liver disease…” (see step e.).
The claimed steps of identifying liver disease by assigning a score by comparing the activity to recited cutoff values, i.e. the percentages recited (see step c.); summing the scores (see step d.); and comparing the summed scores to another cutoff values, i.e. the cumulative assessment score values recited (see step e.), may also be categorized as abstract ideas, namely mental processes/concepts performed in the human mind (such as a doctor simply thinking about the measured level in relation to a cutoff value, summing the score and making an evaluation, judgment, or opinion). The claims, under their broadest reasonable interpretation, cover performance of identifying liver disease solely within the human mind, or by a human using pen and paper. Comparing information regarding a sample to a numerical level (to a cutoff value) represents abstract ideas.
Similar concepts involving comparing information regarding a sample or test subject to a control or target data have been held to be an "abstract mental process", as in University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 113 USPQ2d 1241 (Fed. Cir. 2014) which involved "comparing BRCA sequences and determining the existence of alterations", the collecting and comparing of known information in Classen, the comparing information regarding a sample or test subject to a control or target data in Ambry and Myriad CAFC, as well as Mayo (which also involved specific numerical cutoff levels).
The recited cumulative score values also constitutes abstract ideas (a cutoff value being itself a mathematical concept).
Step 2A, Prong 2
The claims also recite “a. obtaining a blood or plasma sample from the subject; b. measuring by using assays the activities or levels..”. Such steps of providing a sample and measuring the concentration of protein C, factor V, factor VIII, protein S, D-dimer, sP-selectin, and asTF therein are insufficient to integrate the judicial exception(s) 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 protein C, factor V, factor VIII, protein S, D-dimer, sP-selectin, and asTF are recited at a high level of generality and are not tied, for example, to any particular technique, machine or apparatus.
Claims 10, 14 and 17 further recite “f. administering to the subject a treatment” (see step f.)).
Dependent claim 11 recites “wherein the treatment administered to the subject comprises a transplant”.
Dependent claims 12, 15 and 19 recites “wherein the treatment administered to the subject comprises a therapeutic agent”.
Dependent claim 18 recites “wherein the treatment administered to the subject comprises a weight loss program”.
These “treating” steps are insufficient to integrate the judicial exception as (1) they are not limited to a particular treatment, and (2) there is not necessarily any relationship between the judicial exception and the treatment step.
(1) The recited steps of “administering to the subject a treatment” are recited at a high level of generality and are not limited to a particular treatment. Note that “a transplant” (claim 11), “a therapeutic agent” (claims 12, 15 and 19) and “a weight loss program” (claim 18) are not a particular treatment. These are treatments are considered generic. Such highly generalized treatment limitations – which do not require any specific treatment for liver disease – do not amount to sufficient practical application to provide patentability. Although a claim limitation can integrate a judicial exception by applying or using the judicial exception(s) to effect a particular treatment or prophylaxis for a disease or medical condition, in this case no specific or particular treatment is set forth.
The level of generality in the instant claims stands in contrast to the treatment claims found patent-eligible in Vanda Pharm. Inc. v. West-Ward Pharm. Int’l Ltd., 887 F.3d 1117 (Fed. Cir. 2018) and Natural Alternatives Int’l v. Creative Compounds LLC, 2017 WL 1216226 (Fed. Cir. Mar. 15, 2019). The claims at issue in Vanda recited administering a specific drug (iloperidone) at specific dosage ranges based on a patient’s genotype. Vanda, 887 F.3d at 1135. Accordingly, the court found that although the inventors recognized the relationships between iloperidone, a patient’s genotype, and QTc prolongation, what they claimed is “an application of that relationship,” i.e., “‘a new way of using an existing drug’ that is safer for patients because it reduces the risk of QTc prolongation.” Id. (quoting Mayo, 566 U.S. at 87). The Federal Circuit characterized the Vanda claims as being directed to “a specific method of treatment for specific patients using a specific compound at specific doses to achieve a specific outcome.” Id. at 1136. Similarly, the Federal Circuit found that the claims in Natural Alternatives “contain specific elements that clearly establish they are doing more than simply reciting a natural law,” such as specifying a patient population, particular results to be obtained, specific compounds to be administered to achieve the claimed results, and dosages via an “effective” limitation. Natural Alternatives, 4-5.
In contrast to the claims in Vanda and Natural Alternatives, the present claims do not specify a particular result to be obtained, a compound to be administered to achieve a claimed result, or any specific dosage of a specific compound. The recited treating steps do not limit the claims to a particular application; instead, the effect of the treatment limitations “is simply to tell doctors to apply the law somehow when treating their patients.” Mayo, 566 U.S. at 81-82.
Here, the claimed treatment step is instead merely an instruction to “apply” the exception in a generic way. Thus, the treatment step does not integrate the judicial exceptions into a practical application.
(2) Because of the way the claims are currently presented, there is not necessarily any relationship between the judicial exception(s) and the treatment step. The claims do not clearly require that the treatment step be for the liver disease and is open to the possibility that one determines liver disease in step e. and then treats a different disease in step f.. Accordingly, under the broadest reasonable interpretation of the claims, treating step e. is not clearly practical applications of the judicial exception(s) and so fails to integrate the judicial exception(s).
ELIGIBILITY STEP 2B: WHETHER THE ADDITIONAL ELEMENTS CONTRIBUTE AN "INVENTIVE CONCEPT"
The additional elements of the claims, including the steps of providing a blood or plasma sample and measuring the activities or levels of protein C, factor V, factor VIII, protein S, D-dimer, sP-selectin, and asTF therein, do not add significantly more to the judicial exception(s). The step of measuring protein C, factor V, factor VIII, protein S, D-dimer, sP-selectin, and asTF is recited at a high level of generality and is not limited, for example, to any specific testing technique.
In this case, it was well-understood, routine and conventional to provide a blood or plasma sample and measure the activities or levels of protein C, factor V, factor VIII, protein S, D-dimer, sP-selectin, and asTF therein.
See for example, Michelson et al. (US 20140046683 A1)-Cite No. 2 on IDS filed 11/15/2023 (“Michelson”).
Michelson teaches a “the evolution and pathophysiology of the disease process, the response to therapy, and the possible onset of untoward side effects upon exposure to a drug can be monitored by longitudinally sampling blood. From these samples a profile of key circulating biomarkers can be established” (para. 117). Michelson further teaches that “Exemplary liver markers include…Protein C” (para. 142). Michelson further teaches that “Exemplary coagulation status markers include without limitation…Factor V…Factor VIII… Protein C, Protein S, D-dimer” (para. 162).
See also, Sinegre et al. Journal of Thrombosis and Haemostasis, 16: 1132–1140 DOI: 10.1111/jth.14011-Cite No. W of PTO-892 12/19/2024 (“Sinegre”).
Sinegre teaches providing a blood or plasma sample and measuring the activities or levels of protein C, factor V, factor VIII, protein S, D-dimer therein (“Blood was drawn from an antecubital vein” page 1133 col. 2 para. 2, “Coagulation assays were performed with a STA-R Evolution coagulometer” page 1133 col. 2 para. 3, “The results for the main coagulation parameters are summarized in Table 2” page 1134 col. 2 para. 4, see Table 2 page 1135 showing the results).
See also, Vardaeli et al. ( Hepato-gastroenterology, 2007, 54(74):466-469)-Cite No. X of PTO-892 12/19/2024 (“Vardaeli”).
Vardaeli teaches measuring sP-selectin plasma levels in chronic liver disease patients (Abstract).
See also, Caversaccio et al. European Journal of Gastroenterology & Hepatology 2018;pages 1-6)-Cite No. U of PTO-892 12/19/2024 (“Caversaccio”).
Caversaccio teaches providing a blood or plasma sample and measuring the activities or levels of asTF therein (Abstract).
When recited at this high level of generality, there is no meaningful limitation, such as a particular or unconventional machine or a transformation of a particular article, in this step that distinguishes it from well-understood, routine, and conventional data gathering activity engaged in by scientists prior to applicant’s invention, and at the time the application was filed, e.g., the routine and conventional techniques of detecting a protein. See also MPEP 2106.05(g).
Furthermore, there is nothing of record to suggest that the claims involve novel treatment steps. Treating is recited at a high level of generality.
Appending a generic, routine, and obvious post-solution treatment step does not provide a sufficient inventive concept to satisfy § 101. As was the case in Mayo and Ariosa, the method claims at issue here amount to "nothing significantly more than an instruction to doctors to apply the applicable laws when treating their patients" using "conventional steps, specified at a high level of generality." Mayo, 132 S. Ct. at 1298, 1300; Ariosa, 788 F.3d at 1377-78.
In addition, the “treatment” step f. of claims 10, 14 and 17 is also insufficient to add significantly more as it is recited at a high level of generality (no specific treatment is set forth). Broadly or generically treating is tantamount to a mere instruction to “apply” the judicial exception using well-understood, routine or conventional techniques in the field. It does not go beyond general instructions to apply or use the judicial exception. A bare statement of a judicial exception, even a newly discovered judicial exception or very narrowly judicial exception, is not sufficient to integrate the judicial exception such that it is practically applied.
Unlike the claims in Vanda Pharm. Inc. v. West-Ward Pharm. Int’l Ltd (Fed. Cir. 2018, which were directed to a specific method of treatment for specific patients using a specific compound at specific doses to achieve a specific outcome (see Vanda decision at page 32, second paragraph), the instant claims, like those in Mayo, while including a treatment step cannot be clearly categorized as being directed to a specific method of treatment; and the treatment steps fail to add significantly more for reasons noted above.
In this case, step f. along with the limitations of dependent claims 12, 15 and 19, are well-understood, routine and conventional.
See for example Michelson et al. (US 20140046683 A1)-Cite No. 2 on IDS filed 11/15/2023 (“Michelson”).
Michelson teaches that “[i]n some instances, the medical action involves at least one action selected from the group consisting of altering a dosage of an existing therapeutic agent administered to said subject, administering a different a therapeutic agent, and administering a different combination of therapeutic agents” (para. 17).
See also Riley et al. (AAFP, 2001, vol. 64 no:10 pages 1735-1740) Cite No. V of PTO-892 12/19/2024 (“Riley”).
Riley teaches throughout the publication treatment strategies in chromic liver disease that includes medication, diet and surgery as for example transplant in most advanced stages (Abstract, whole publication).
See also Jia (WO 2017210147 A1)-Cite No. N of PTO-892 12/19/2024. Jia teaches in paragraph 179 therapeutics, including metformin, and weight loss programs for treating liver disease.
Furthermore, the limitation “wherein the treatment administered to the subject comprises a weight loss program” is well understood, routine and conventional in the art. See also for example Michelson paragraph 216, “[T]he feedback may assist with behavior modification and increase compliance with therapy. The algorithms described herein enable correlation of blood data to efficacy dynamics profiles, behavior, lifestyle, diet, and side-effects”.
See also Ko et al. (WO 2018105921 A2) (“Ko”). Ko teaches that therapeutics as well as a weight loss program are well-known treatments for liver disease (“On the other hand, the effect of fatty by the administration of some diabetes or obesity drugs is known, and among them, Orlistat, which is used as an oral obesity agent, reports that the recovery of liver tissue is improved in patients with fatty liver. There is. In addition, has been reported to reduce blood liver enzyme levels and hepatic necrotic inflammation and fibrosis in nonalcoholic fatty liver patients without diabetes, and is an of peroxisome proliferator-activated receptor (PPAR). Thiazolidinedione (TZD) family of drugs has been reported to inhibit fat accumulation in the liver and muscle and to exhibit direct anti-fibrotic activity against the liver in animal models of nonalcoholic fatty . However, despite the development of such therapeutic drugs (Korean PatentLaid-Open Publication No. 10-2013-0103190), there is a shortage of useful drugs for treating fatty , and since there is no established for fatty , only proper exercise and are recommended” page 3 para. 4).
Regarding dependent claim 11, “wherein the treatment administered to the subject comprises a transplant”, is also considered to be well-understood, routine and conventional in the art.
See, for example, O’Leary et al. GASTROENTEROLOGY 2008;134:1764–1776 (“O’Leary”). O’Leary teaches that “[p]atients should be considered for liver transplantation if they have evidence of fulminant hepatic failure, a life-threatening systemic complication of liver disease, or a liver-based metabolic defect or, more commonly, cirrhosis with complications such as hepatic encephalopathy, ascites, hepatocellular carcinoma, hepatorenal syndrome, or bleeding caused by portal hypertension.” (Abstract). O’Leary further teaches that “[t]he Clichy criteria utilize the grade of hepatic encephalopathy and serum factor V activity, with transplantation recommended for patients with grade 3 or 4 encephalopathy or factor V levels less than 20% of normal” (page 1772 co.1 para. 2).
Furthermore, see Riley et al. (AAFP, 2001, vol. 64 no:10 pages 1735-1740) Cite No. v of PTO-892 12/19/2024 (“Riley”). Riley teaches throughout the publication treatment strategies in chronic liver disease that includes medication and surgery as for example transplant in most advanced stages (abstract, whole publication).
See also Jia (WO 2017210147 A1)-Cite No. N of PTO-892 12/19/2024 paragraph 187 “[f]or example, a liver transplant can be reserved for subjects having the most relatively severe or latest stage fibrosis”.
For all of these reasons, the claims fail to include additional elements that are sufficient to amount to significantly more than the judicial exception(s).
New Rejections
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, 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.
Claims 10-20 are rejected under 35 U.S.C. 103 as being unpatentable over Lewis et al. (Blood, November 19, 2018,132 Supplement 1 :3784)-Cite No. U of PTO-892 12/19/2024 (“Lewis”) in view of Jia (WO 2017210147 A1)-Cite No. N of PTO-892 12/19/2024 .
Note that Lewis is considered prior art because the instant claims fail to receive priority benefit to the provisional application No. 62/714,161, filed 8/3/2018 (see Priority section above).
Although the reference by Lewis was published within the grace period of the 371 application (PCT/US19/45092 effectively filed on 08/05/2019) and includes all of the inventors in the present application, this reference does not fall into the 102(b)(1)(A) exception because the Lewis publication includes another author not listed in the present application, specifically: Marc Vasse.
Regarding claims 10-20, although the claim is indefinite (see 112b rejection above), in the interest of compact prosecution, the percentages claimed (see step c.) are interpreted to be the activity or level of protein in relation to a control.
Lewis teaches a method for identifying severe liver disease, a method for identifying moderate liver disease or a method for identifying a least severe level of liver disease in a subject (“A Novel Plasma Panel for the Assessment of Chronic Liver Disease Severity” Title), the method comprising: a. obtaining a blood or plasma sample from the subject (“Blood was collected via venipuncture (0.129 mol/I sodium citrate) from CLO patients suffering from cirrhosis due to untreated HCV and/or excessive alcohol consumption, that were previously assigned a CP score: CP-A, n=12; CP-B, n=19; CP-C, n=11. Healthy control subjects (n=30) were age and sex matched;” Methods); b. measuring by using assays the activities or levels of the following seven proteins from the sample: protein C, factor V, factor VIII, protein S, D-dimer, sP-selectin, and alternatively spliced Tissue Factor (asTF) (“Of the 14 remaining parameters investigated in CLO and control plasma, the levels of fVIII, D-dimer, and asTF increased with CLO severity while protein C, fV, protein S, and sP-selectin levels decreased (Table 1)” Results page 2 para. 2); c. assigning a score to each of the seven protein activities or levels as follows: i. a protein C activity >65% is assigned a score of 0, a protein C activity of 35-65% is assigned a score of 1, and a protein C activity <35% is assigned a score of 2; ii. a factor V activity >80% is assigned a score of 0, a factor V activity of 55-80% is assigned a score of 1, and a factor V activity <55% is assigned a score of 2; iii. a factor VIII activity < 140% is assigned a score of 0, a factor VIII activity of 140-200% is assigned a score of 1, and a factor VIII activity >200% is assigned a score of 2; iv. a protein S activity >50% is assigned a score of 0, and a protein S activity <50% is assigned a score of 2; v. a D-dimer level <0.5 ng/ml is assigned a score of 0, a D-dimer level of 0.5-1 ng/ml is assigned a score of 1, and a D-dimer level > 1 ng/ml is assigned a score of 2; vi. a sP-selectin level > 100 pg/mL is assigned a score of 0, a sP-selectin level of 50-100 pg/mL is assigned a score of 1, and a sP-selectin level <50 pg/mL is assigned a score of 2; and vii. an asTF level <0.3 pg/mL is assigned a score of 0, an asTF level of 0.3-0.5 pg/mL is assigned a score of 1, and an asTF level >0.5 pg/mL is assigned a score of 2 (“and in combination, these 7 parameters were able to predict the previously assigned CP scores with high accuracy. Our scoring system assigns a numeric value (0, 1, or 2) for each parameter; a cumulative score of <2 is normal, 2-3 CP-A, 4-7 CP-B, and 28 CP-C (Table 2)” Results page 2 para. 2, see Table 2); d. summating the assigned scores of the seven proteins to obtain a cumulative assessment value and e. determining the presence of severe liver disease in the subject based on a cumulative assessment value of 8 or greater, e. determining the presence of moderate liver disease in the subject based on a cumulative assessment value of 4-7 or e. determining the presence of a least severe level of liver disease in the subject based on a cumulative assessment value of 2-3 (“a cumulative score of <2 is normal, 2-3 CP-A, 4-7 CP-B, and 28 CP-C (Table 2). The system was 97.2% accurate at predicting the CP score: of the 72 plasma samples analyzed, there was only one false positive (a control scored as a CP-A), and one CP-C sample scored as CP-B” )” Results page 2 para. 2, see Tables 1-2 page 3). Note that although Lewis fails to use the language “severe liver disease”, “moderate liver disease” and “a least severe level of liver disease”, the teachings of the Child-Pugh (CP) scoring system, namely the “CP-A, n=12; CP-B, n=19; CP-C, n=11” scores (see Methods and Tables 1-2 of Lewis) inherently provides the “severe liver disease”, “moderate liver disease” and “a least severe level of liver disease” because these CP scores correspond to the claimed liver disease severity (see instant specification paragraph 9 disclosing that “b) a cumulative assessment value of 2-3 is the least severe level of liver disease, comparable to Child-Pugh-A; c) a cumulative assessment value of 4-7 is a moderate level of liver disease, comparable to Child-Pugh-B; and d) a cumulative assessment value of 8 or greater is the most severe level of liver disease, comparable to Child-Pugh-C”).
Lewis is silent regarding step f. administering to the subject a treatment, wherein the treatment administered to the subject comprises a transplant, wherein the treatment administered to the subject comprises a therapeutic agent, wherein the therapeutic agent is selected from the group consisting of metformin, ursodiol, pioglitazone and ppar-gamma agonists; and wherein the treatment administered to the subject comprises a weight loss program.
Jia teaches “liver disease-related biomarkers and methods of use thereof” (Title). Jia further teaches “treating subjects evaluated by diagnostic methods of the invention” (Abstract). Jia further teaches that “[a]n objective assessment of the severity of liver disease in chronic liver disease patients has become increasingly important, such as in decision making prior to treatment and for evaluating patients with mild disease who are not being treated but are rather being followed up expectantly. As liver fibrosis/cirrhosis prevalence increases, it challenges clinicians to identify its progression” (para. 4). Jia further teaches administering to the subject a treatment, wherein the treatment administered to the subject comprises a transplant, wherein the treatment administered to the subject comprises a therapeutic agent, wherein the treatment administered to the subject comprises a weight loss program (“the treatment comprises administering a therapeutic agent, performing surgery (e.g. liver transplantation)…prescribing a diet (e.g. lowering calorie or carbohydrate intake), discontinuing alcohol consumption, prescribing exercise, or prescribing a therapeutic regimen for weight-loss” para. 164). Jia further teaches wherein the therapeutic agent is selected from the group consisting of metformin, ursodiol, pioglitazone and ppar-gamma agonists (“Treatments useful in the present invention can include, for example, antidiabetic agents (e.g. metformin, rosiglitazone, or pioglitazone),” para. 179). Jia further teaches that “[u]seful treatments include a treatment that ameliorates or reduces the liver disease status, prevents or slows the progression of the liver disease status, or prevents or slows the development of another condition that can be caused by the liver disease status” (para. 162). Jia further teaches that “[t]he use of a therapy in the treatment of a subject identified as having a liver disease status by a diagnostic method of the invention, can involve any therapy, any liver disease status, and any biomarker panel taught herein” (para. 163). Note that although Jia fails to explicitly teach that the transplant treatment is for severe liver disease; or that the therapeutic agent, e.g. metformin, is for severe, moderate and a least severe liver disease; or that the weight loss program is for a least severe liver disease; the teaching that any treatment can be used for any liver disease status (para. 163) inherently provides wherein the transplant treatment is for severe liver disease; wherein the therapeutic agent, e.g. metformin, is for severe, moderate and a least severe liver disease; and wherein the weight loss program is for a least severe liver disease.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Lewis to include administering to the subject a treatment, wherein the treatment administered to the subject comprises a transplant (for severe liver disease), a therapeutic agent, i.e. metformin (for severe, moderate and a least severe liver disease) and a weight loss program (for a least severe liver disease) as taught by Jia because Jia teaches that these treatments ameliorate or reduce the status of the liver disease, slow the progression of the liver disease and prevent further complications of the disease and Lewis is interested in studying liver disease severity. Furthermore, Jia teaches that assessing liver disease severity and then administering a treatment is important because it enables the appropriate treatment to the patient. Therefore, a person would be motivated to include these treatment steps in the method taught by Lewis. A person having ordinary skill in the art would have had a reasonable expectation of success because both Lewis and Jia are directed to biomarkers for liver disease severity. Furthermore, Jia suggests that the treatments are effective for any liver disease severity.
Response to Arguments
Applicant's arguments filed 6/20/2025 have been fully considered but they are not persuasive.
Regarding the 101 rejections,
Applicant argues that “ Each independent claim includes the required step of administering treatment, which is neither a natural phenomenon nor an abstract idea. Specifically, the claims now satisfy Step 2A, Prong 2. The claims recite additional elements that integrate the exception into a practical application of the exception. In the new claims, the treatment step is performed in response to the score level” (page 3 para. 1).
However, contrary to Applicant’s argument, the recited treatment step fails to satisfy Step 2A, Prong 2 because the treatment steps are insufficient to integrate the judicial exception as (1) they are not limited to a particular treatment, and (2) there is not necessarily any relationship between the judicial exception and the treatment step (see 101 rejection above for the full analysis).
Regarding the 103 rejections,
Applicant argues that “Lewis reference is not available as prior art. Lewis was published in November 2018, two months after the priority date of provisional application 62/714, 161. As described above, Applicants are submitting a petition to restore the benefit of provisional application 62/714, 161 in conjunction with this response” (page 3 para. 2).
However, contrary to Applicant’s remark, Lewis is considered prior art because the instant claims fail to receive priority benefit to the provisional application No. 62/714,161, filed 8/3/2018 (see Priority section above). The instant claims contain subject matter that was not disclosed in the 62/714, 161 application. Because of this, the claims have an effective filing date of 8/5/2019, which is the filing date of the PCT/US19/45092 application.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/Fernando Ivich/Examiner, Art Unit 1678
/CHRISTOPHER L CHIN/Primary Examiner, Art Unit 1677
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