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 .
Any objection or rejection which is not reiterated or otherwise addressed was overcome by amendment to the claims filed 7/2/2026.
Claim Objections
Applicant’s remarks on p. 6 of the response filed 7/2/2026 were persuasive to overcome the objection for claims 11 and 12. New rejections are set forth to address the amended claims.
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 1, 3-10 and 15-16 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 claim(s) contains 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.
Claim 1 has been amended to recite “preventative intervention for reducing the risk of liver cancer” and “enhanced liver cancer surveillance.” Neither of these phrases have adequate written description; this is a rejection for new matter.
The response points to paragraphs 28 and 29 as support for these amendments (response p. 8, 3rd full ¶). Neither of these paragraphs provide express basis for the newly added limitations.
Paragraph 28 teaches examining patients evaluated to have high risk of developing liver cancer at “higher frequencies” than subjects evaluated to have low risk. But it does not teach “enhanced” surveillance which could include increasing frequency as recited in the specification, but also could include using more sensitive tests or something else. The scope of “enhanced liver cancer surveillance” is broader than the disclosure.
Paragraph 29 provides a method for “preventing” liver cancer which is narrower than the current amendment in that it teaches preventing liver cancer by “administering a drug for preventing the development of liver cancer.” The instant claim amendment encompasses any “preventative intervention” which is much broader than “a drug” and encompasses potentially changes in diet and lifestyle, or surgery for example.
Therefore the claims are rejected as having new matter.
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 1, 3-10 and 15-16 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.
The phrased “enhanced surveillance” in claim 1 is indefinite because it is a relative term with no basis for comparison or definition. It is unclear what makes one surveillance enhanced relative to another.
Claim 1 recites that it is a method for “preventing the development of liver cancer in the subject” but clearly encompasses embodiments where no preventative intervention occurs. It is unclear how, in those embodiments, the method is reasonably considered a method of preventing liver cancer in the subject.
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.
Claims1, 3-10 and 15-16 are rejected under 35 U.S.C. 101 because the claimed invention is directed to natural phenomenon and an abstract idea without significantly more.
The claim(s) recite(s) that the naturally occurring GDF15 level is related to the risk of developing liver cancer; this is a natural phenomenon which has been recognized by the courts as a judicial exception. Further, the claims recite “evaluating risk” and “relating … to identify” the level to the risk which are themselves mental process abstract ideas. Claim 3 and those that depend form it set forth an additional abstract idea of comparing the GDF15 level to a “cutoff value.” This is a mathematical concept and a mental process abstract idea.
This judicial exception is not integrated into a practical application because the claims do not apply or use the judicial exceptions in any way.
Claim 1 has been amended encompasses step (3)(i) where no further action is required- therefore the claim in this embodiment does not use or apply the judicial exception in any way. The judicial exceptions are not integrated.
Furthermore, step (3)(ii) recites “preventative intervention” at such a high level of generality that it does not integrate the judicial exception; it is a mere statement to “apply it”. The treatment is not specific. Further, the encompassed “enhanced” surveillance does not affect treatment or prophylaxis of liver cancer, and also does not integrate the judicial exceptions. The only other step in addition to the judicial exception is a step of measuring a GDF15 level of a subject, and this step is a data gathering step necessary to do the relating and does not apply or use the exception in any way.
The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the step in addition to the judicial exception is a step of measuring GDF15 in a subject. It is recited at such a high level of generality that it merely invites the skilled artisan to use any available tool, like ELISA to measure the GDF15 level in any sample, which methods were known in the art, see specification paragraph 35 which teaches ELISA was known since 1980 and methods for GDF15 transcription detection such as RT-PCR since at least 1992. Additionally, there is no further required action in step (3) if the subject is identified as not having high risk of developing liver cancer. Therefore considered as a whole, the additional steps do not add significantly more to the judicial exceptions.
Furthermore, with regard to claims 4 and 8 in particular, determining the GDF15 level of patients in the plasma was well known at the time of the invention, see at least Halim and Liu cited in the IDS.
Response to Remarks
Applicant argues that the third step integrates the judicial exception into a practical application. However, the third step fails to do so for the reasons set forth in the rejection.
Claim Rejections - 35 USC § 102
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.
Claim(s) 11-12 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Liu et al. ((2015) Association of Serum Level of Growth Differentiation Factor 15 with Liver Cirrhosis and Hepatocellular Carcinoma. PLoS ONE 10(5): e0127518; cited in IDS).
Regarding claims 11 and 12, Liu et al. each a specific ELISA kit which employs capture and detection antibodies for the specific detection of GDF15 (p. 3).
Response to Remarks
The amendment to the claims overcame the rejection of claim 1 and those that depend form it. With regard to claims 11 and 12, claims 11 and 12 do not depend from claim 1, they merely refer to claim 1 to set forth the intended use of the claim. See MPEP 2173.05(f). There is no structure in the claim that distinguishes from the antibodies taught in the reference. The rejection is maintained.
Claim(s) 11-12 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Myojin et al. (Aliment Pharmacol Ther. 2022;55:422–433).
This reference is available as of its publication date which was 23 November 2021.
A certified translation of Japanese Patent Application 2021-121873 was provided with the response. The rejected claims are not entitled to benefit of the foreign priority date because the foreign priority document does not provide basis for newly added step (3) of claim 1.
Therefore, the effective filing date of the instant claims is 7/26/2022, the date that the PCT application was filed, and the Myojin et al. application is available as prior art. Further, it is noted that although Myojin et al. includes all three of the instant inventors as authors, it includes many other additional inventors as authors, as well.
The reference teaches using ELISA to test GDF15 levels in serum. ELISA inherently uses an antibody and the ELISA kit mentioned in section 2.4 anticipates claims 11 and 12.
Response to Remarks
Since the Foreign Priority document does not provide adequate support for the entirety of the claims, the claims do not get benefit of the filing date.
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.
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.
Claim(s) 1, 3, 4, 5, 6, 7, 8, 9, 10, 14, 15, and 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Myojin et al. (Aliment Pharmacol Ther. 2022;55:422–433) in view of Baumert et al. (US 20230313299 A1).
The Myojin reference is available as of its publication date which was 23 November 2021.
A certified translation of Japanese Patent Application 2021-121873 was provided with the response. The rejected claims are not entitled to benefit of the foreign priority date because the foreign priority document does not provide basis for newly added step (3) of claim 1. Therefore, the effective filing date of the instant claims is 7/26/2022, the date that the PCT application was filed, and the Myojin et al. application is available as prior art. Further, it is noted that although Myojin et al. includes all three of the instant inventors as authors, it includes many other additional inventors as authors, as well.
The reference teaches the claimed method steps 1 and 2, see Abstract and throughout.
The reference does not teach step 3 of the claimed methods.
Baumert teaches that preventing or delaying onset of HCC in a subject in a subject identified as at high risk of developing HCC by administering a treatment to a subject diagnosed as at risk for developing HCC (¶136-138). Baumert teaches that chemoprevention is the use of drugs to reduce the risk or prevent the development of HCC (¶0028).
Therefore, it would have been obvious to modified the method taught by Myojiin and have treated patients at risk for developing HCC with a drug to prevent or delay the onset of HCC, as motivated by the direct teaching by Baumert.
Claim(s) 1, 3, 4, 5, 6, 7, 8, 9, 10, 14, 15, and 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. in view of Kanwal et al. (Gastroenterology 2017;153:996–1005; cited in IDS) and Baumert et al. (US 20230313299 A1).
Liu teaches that GDF15 is a serum biomarker of HCC and its overall performance is satisfactory. The reference teaches that it appears promising to combine GDF15 with other biomarkers and imaging methods to improve the diagnosis of HCC (p. 10-11). The method taught by Liu includes measuring a GDF15 level of a subject and relating the GDF15 level to the risk of developing liver cancer. Namely Liu et al. teaches serum GDF15 levels were increased in patients with HCC compared with healthy controls, see abstract and throughout. Additionally, Lui teaches that combined use of AFP and GDF15 increases the diagnostic sensitivity and specificity for GDP15 (p. 6). Liu teaches that an area under the curve for GDF15 with an optimal cutoff value of 1.945 ng/mL (p. 6, figure 4B). Liu teaches a cutoff of 20 ng/mL for separating patients into two groups according to AFP (p. 6).
With regard to claims 4 and 8, Liu et al. teaches measuring GDF15 protein in serum by ELISA. See p. 3.
With regard to claim 3, this claim does not require any further action, the lengthy “wherein” clause sets forth a required inherent property of the relationship between the GDF15 level relative to “a cutoff value.” The reference teaches that levels above a cutoff have increased risk, see p. 5, first full paragraph, and Liu et al. teaches setting a cutoff value based on ROC analysis, see p. 5, first full paragraph.
With regard to claim 6, this claim limits how the cutoff value is “set,” which refers back to the “wherein” clause of claim 3 which does not modify the action of the claim; it refers to the fact that the cutoff level was “set in advance.”
Liu et al. does not teach screening a patent who has not developed liver cancer after achieving sustained virologic response (SVR) from HCV, and Liu et al. does not teach treating a patient identified as having a risk for disease to prevent HCC.
Kanwal et al. teach that patients who have achieved SVR and have underlying cirrhosis should be screened for HCC after SVR. The suggestion to “screen” for HCC fairly encompasses screening patients who have not yet developed cancer. Kanwal et al. further teaches that FIB-4 is a predictor variable that is a biomarker of liver fibrosis (p. 997, 2nd column). Kanwal et al. teaches using the FIB-4 as part of a model for risk stratification for HCC (p. 998). The reference teaches that patients with FIB-4 between >3.25 have the highest HCC incidence (p. 1000, 1st column).
At the time of the invention, it was common to develop biomarkers for predicting risk for disease by detecting the biomarker in case and control patients. For example, Baumert et al. teach detecting differential expressions of gene markers in patients who have HCC versus those who do not, and identifying biomarkers (See examples). Baumert specifically teach using such identified markers for the diagnosis of liver disease risk in a patient (See Abstract, p. 32, Claim 1). Furthermore, Baumert teaches that preventing or delaying onset of HCC in a subject aby administering a treatment to a subject diagnosed as at risk for developing HCC (¶136-138). Baumert teaches that chemoprevention is the use of drugs to reduce the risk or prevent the development of HCC (¶0028).
Therefore, it would have been obvious to have applied the method for detecting GDP15 which is associated with HCC taught by Liu to the patients having achieved SVR and having cirrhosis taught by Kanwal. It would have been obvious to do this on order to monitor these patients for HCC since Kanwal teaches that they are at increased risk for developing HCC despite achieving SVR and Liu et al. teaches that GDP15 is elevated in patients having HCC. Liu clearly related the presence of increased GDP15 to the presence of HCC, so detecting elevated GDP15 would have necessarily been related to the possibility (or risk) that HCC is developing or undetectably present in patients who had not yet developed the HCC. This is supported by Buamert who also teach a biomarker for HCC identified in patients with and without HCC and teach that it can be used to identify risk of developing HCC. Furthermore, it would have been obvious to have treated patients at risk for developing HCC with a drug to prevent or delay the onset of HCC, as motivated by the direct teaching by Baumert.
Regarding claim 7, the cutoff value is further defined, but as addressed above, this limitation limits the “wherein” clause first set forth in claim 3, which does not itself require any further active step but instead sets forth an inherent relationship between the level of GDP15 and risk. Furthermore, it is noted that 1.945 ng/mL taught in Liu as a cutoff is about 1400 pg/mL.
Regarding claims 9 and 10, as discussed previously the claim is indefinite. Furthermore, like in prior claims, the cutoffs limit a portion of the claim that appears to state an inherent property and not require any further active step.
Response to Remarks
Applicant argues that Liu only discloses that GDF15 can only be used as a detection or diagnosis marker for HCC when an individual already has HCC. Liu does not teach that it can only be used in individuals who already have HCC. In fact Liu specifically teaches that the findings presented “have value in screening HCC risk in early, large population” (p. 10). None of the cited references state that a biomarker that was identified in a patient population cannot be used to predict risk of disease in patients not yet diagnosed with disease. And Liu and Buamert both suggest a use in that direction.
A new rejection is written to address the amended claims. Although a diagnostic marker and a risk biomarker may be different, Baumert demonstrates that before the effective filing date one skilled in the art would have also used markers identified as differentially expressed in cases and controls to predict risk of disease in patients who do not have disease.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Habibzadeh teaches that test cut-off values can be calculated using a variety of techniques, one of the most common techniques for determining a cutoff for a continuous variable being the point where Youden’s index is maximum (Abstract, p. 299, 2nd column).
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Juliet Switzer whose telephone number is (571)272-0753. The examiner can normally be reached Monday to Thursday, 8:00 AM-3:30 PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Winston Shen can be reached at (571)-272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Juliet Switzer
Primary Examiner
Art Unit 1682
/JULIET C SWITZER/Primary Examiner, Art Unit 1682
