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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on October 2, 2025 has been entered.
Claim Objections
Claims 17 and 18 are objected to because of the following informalities:
“wherein each of the first antidepressant, the second antidepressants being different from the first antidepressant is selected from the group consisting of” would be more precisely rewritten as “wherein each of the first antidepressant and second antidepressant, the second antidepressant being different from the first antidepressant, is selected from the group consisting of”
Appropriate correction is required.
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 1, 4-7, 9-12, 17, and 18 are rejected under 35 U.S.C. 101 because the claimed invention is directed to abstract ideas and natural phenomenon without significantly more. The claim(s) recite(s) methods comprising measuring biomarkers, the concentration of which is correlated to depressive disease remission, and thus recites a natural phenomenon. Further, the claims recite determining whether there is an acute phase remission performed by comparing the measured concentration of each of the four antidepressant treatment response prediction biomarkers to a preset cutoff level which is a step that can be accomplished entirely in the mind; and, thus, a mental process. Moreover, claim 7 recites a mathematical formula, or another abstract idea. These judicial exceptions are not integrated into a practical application because the step of measuring the biomarkers is merely an extra-solution activity. Claims 1 and 7, while no longer reciting treating as a contingent step, do recite treatment options as alternatives, one of which is “an alternative pharmacological regimen”. It is noted below that alternative pharmacological regimens is indefinite and no limiting definition is provided in the instant Specification. Alternative pharmacological regimens is interpreted as encompassing plant or herbal derivatives or psychedelic drugs such as ketamine.
MPEP 2106.04(d)(2)(a) states that in order for a treatment to integrate a judicial exception, the treatment must be particular. The recitation of a vague and broad category of “an alternative pharmacological regimen” which is interpreted to include therapeutics which would not be conventionally used in the treatment of depression nor known in the art, as a whole, to reduce the level of the four antidepressant treatment response prediction biomarkers. This treatment is, therefore, general and merely instructs one to apply the judicial exception in a generic way. Thus, the step of administering does not integrate the judicial exception.
The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the method does not recite further steps beyond the insignificant extra-solution activity of measuring, the mental process of determining which comprises the mathematical formula of claim 7, and the step of treating which includes a generic treatment.
Claim Rejections - 35 USC § 112(b)
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, 4-6, 7, 9-12, 17, and 18 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 9 and 10 are indefinite as being incomplete by its dependence on cancelled claim 8. See MPEP 608.01(n). Claims 11 and 12 are rejected for depending from claims 9 and 10.
Claims 1 and 7 recites treatments in the alternative for patients lacking a probability of remission and one treatment is “an alternative pharmacological regimen”. There is no limiting definition in the instant disclosure. Alternative treatments for depression appear in the art and appear to encompass plant-derivatives (St. Johns wort, for example), supplements (including omega-3 fatty acids or folate, for example), or psychedelics (ketamine or cannabinoids, for example); see Nahas et al. (Canadian Family Physician. 57(6): 659-663; Published: June 2011), Shelton et al. (CNS Drugs. 24: 131-161: Published: August 29, 2012), and Niciu et al. (Annual Review of Pharmacology and Toxicology. 54: 119-139; Published: January 2014).
It is unclear where the metes and bounds of an alternative pharmacological regimen lie. Is an alternative pharmacological regimen any substance or composition not indicated or FDA approved for use in depression? Does it have to have been tested in some capacity for use in depression? For the purpose of compact prosecution, the limitation alternative pharmacological regimen, is interpreted as any substance or composition which has not been FDA approved for the treatment of depression.
Claims 4-6, 9-12, 17, and 18 are also rejected for depending from claims 1 and 7 and failing to remedy the indefiniteness.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 9-12 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Because claims 9 and 10 depend from a cancelled claim, the claims fail to incorporate by reference all the limitations of the claim to which they refer. Similarly, because of the dependency upon cancelled claim 8, claims 9 and 10 fail specify a further limitation. Claims 11 and 12 are rejected for depending from claims 9 and 10.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claims 1 and 4-6 are rejected under 35 U.S.C. 103 as being unpatentable over Cattaneo et al. (Neuropsychopharmacology. 38: 377-385; Published: September 19, 2012), Corradi et al. (Revista De Medicina. 96 (2): 103-115; Published: September 6, 2017), Kaldate et al. (WO 2016/160484 A1; Published: October 6, 2016), and Rapaport et al. (Molecular Psychiatry. 21: 71-79; Published: March 24, 2015).
Claim 1 recites measuring the concentration of one or more of hsCRP, IL-6, IL-1β, or leptin, determining the probability of remission based on the comparison of the measured biomarker concentration to a preset cutoff level, and treating with either: a second antidepressant, a combination of antidepressants, the first antidepressant combined with an augmenting drug, or an alternative pharmacological regime.
Cattaneo et al. teaches patients with MDD who achieved responder status, assessed by a reduction in MADRS score of greater than 50% from baseline, at 12 weeks of treatment with escitalopram had lower levels of IL-1β mRNA at baseline compared to non-responders; see page 379 left column and Table 2. Further, Cattaneo et al. teaches that IL-1β mRNA level could be used to predict antidepressant response. Note that acute phase remission is exemplified on page 26 of the Specification, but this is not a limiting definition.
Cattaneo et al. does not teach measuring the level of the cytokine itself, nor comparing to a preset cutoff level, nor alternative treatment strategies when patients are predicted to be non-responders.
Similarly, Corradi et al. teaches that baseline inflammatory markers, including IL-1β and IL-6 could be used to predict antidepressant response; see Abstract and page 105.
While both Cattaneo et al. and Corradi et al. teach the use of IL-1β or IL-1β mRNA as a predictor for antidepressant response, neither reference teaches a method of how to use IL-1β or IL-1β mRNA to predict response.
Kaldate et al. teaches a method of diagnosing various psychiatric disorders, such as bipolar disorder, comprising obtaining a sample and testing for the level of one or more biomarkers, comparing the test level with a reference level, and diagnosing the patient with the disorder based on the comparison; see claim 1 for example. In paragraphs 0161-0163, Kaldate et al. teaches that these biomarkers provide a means to predict therapeutic response, including failure to respond.
Cattaneo et al. and Corradi et al. teach the use of IL-1β and IL-6 as biomarkers for predicting antidepressant response. Neither reference teaches measuring leptin or hsCRP as a biomarker of antidepressant response.
Regarding claim 5, Cattaneo et al. teaches that combining more than one biomarker provides the best predictive model; see Table 3. Rapaport et al. teach high baseline IL-6, hsCRP, and leptin are correlated with a non-responsiveness; see Abstract.
Given the Cattaneo et al. and Corradi et al. teaches that lower IL-1β and IL-1β gene expression at baseline is associated with antidepressant response at 12 weeks and suggests that it may be used as a predictive biomarker for treatment response and Kaldate et al. teaches a method of diagnosing psychiatric disorders, which can also be used to predict treatment response, comprising measuring a biomarker in a biological sample and comparing that level with a reference level, it would have been obvious to one of ordinary skill in the art to measure the level of IL-1β and compare that concentration to a preset cutoff level or reference level, wherein a concentration less than the reference level is predictive of antidepressant response. Further, when a patient is predicted to be a non-responder, it would have been obvious to modify the treatment strategy, including changing the antidepressant or adding an augmenting drug.
Given that Corradi et al. and Rapaport et al. (see Abstract) teach combining more than one biomarker provides the best predictive result and that high baseline IL-1β, IL-6, hsCRP, and leptin are correlated with a non-responsiveness, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to measure more than one or up to four of IL-1β, IL-6, hsCRP, and leptin when assessing potential antidepressant responsiveness. One would have been motivated to measure more than one biomarker because Corradi et al. teaches that combining more than one will yield more reliable results.
Further, regarding the limitation “wherein, in the determining, as the number of the antidepressant treatment response prediction biomarkers, […]” in claim 5, this clause has been fully considered in context of the entire claim, but does not render the claimed method patentable distinct from a method taught by the prior art because it simply expressed the intended result of a process step positively recited. See MPEP 2111.04, which states that a “‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’” Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)).”
With regard to claim 4, the references do not give precise numbers that are used to determine cutoffs to distinguish positive from negative samples. However, it has long been settled to be no more than routine experimentation for one of ordinary skill in the art to discover an optimum value of a result effective variable. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation." Application of Aller, 220 F.2d 454, 456, 105 USPQ 233, 235-236 (C.C.P.A. 1955). "No invention is involved in discovering optimum ranges of a process by routine experimentation." Id. at 458, 105 USPQ at 236-237. The "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." Application of Boesch, 617 F.2d 272, 276, 205 USPQ 215, 218-219 (C.C.P.A. 1980). One skilled in the art would have known to use standards to establish thresholds for distinguishing positive from negative cases. Thus, the recited threshold values of the claims would be arrived at by routine experimentation by one of ordinary skill in this art. Moreover, the values recited in claim 4 are results effective variables as they determine the diagnostic assay result, positive or negative diagnosis for example.
Claim 6 does not require any further action be taken and merely recites a result which naturally flows from the method of claims 1 and 5.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Cattaneo et al. (Neuropsychopharmacology. 38: 377-385; Published: September 19, 2012), Corradi et al. (Revista De Medicina. 96 (2): 103-115; Published: September 6, 2017), Kaldate et al. (WO 2016/160484 A1; Published: October 6, 2016), and Rapaport et al. (Molecular Psychiatry. 21: 71-79; Published: March 24, 2015) as applied to claim(s) 1 and 4-6 above, and further in view of Dremencov et al. (Biological Psychiatry. 61(5): 671-678; Published: August 24, 2006).
The teachings of Cattaneo et al., Corradi et al., Kaldate et al., and Rapaport et al. as related to claim(s) 1 and 4-6, from which these claims depend are given previously in this Office action and are fully incorporated here.
While Corradi et al. suggests augmenting therapy when markers indicate a low responsiveness to antidepressants (ss Perspective for Future Studies section), the reference does not suggest any particular augmenting drugs.
Dremencov et al. teaches the augmentation of escitalopram by co-administration with risperidone.
Given that Corradi et al. teaches adding an augmenting drug and Dremencov et al. supports adding the augmenting drug risperidone to patients with treatment-resistant depression taking escitalopram, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success adding the augmenting drug risperidone to the antidepressant escitalopram.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Response to Arguments
Applicant’s amendments filed October 2, 2025 are acknowledged. Any rejection not repeated above is resolved by amendment.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Applicant argues that Cattaneo et al. measures mRNA expression of IL-1β, not serum concentration of IL-1β.
It is true that Cattaneo et al. measures IL-1β mRNA from blood samples. One of ordinary skill in the art would expect that increased IL-1β mRNA cooccurs with increased IL-1β cytokine expression. Indeed, Corradi et al., also cited in the above rejection, teaches that high levels of IL-1β cytokine is associated with antidepressant non-responsiveness.
Applicant argues that the instant claims “require measuring specific biomarkers (hsCRP, IL-1β, IL-6, leptin) in serum and comparing to defined cutoff values (e.g., hsCRP ,0.61 mg/dL, IL-1β <1.13 pg/mL)” and Cattaneo et al. does not present any actionable thresholds.
First, neither claims 1 nor 17 require that the biological sample be serum. Second, claim 1 and 17 only require the measurement of a single biomarker. And, third, while claims 1 and 17 do require a comparison to a cutoff value, that do not require defined cutoff values. Indeed, defined cutoff values are not recited until claim 4. Claim 4 has not been rejected under 35 U.S.C. 103.
Applicant alleges that Examiner previously acknowledged the unpredictability of biomarker use in depression, noting that not all biomarkers are predictive and results vary by population and treatment.
The alleged acknowledgement of unpredictability of biomarker use in depression is taken out of context. Claim 1 was previously drawn to the use of any biomarker – not limited to hsCRP, IL-1β, IL-6, leptin – and at any time period from baseline – not up to 12 weeks - as currently claimed. The statement of unpredictability with context is provided below:
There is no disclosure of a correlation between structure and function that would allow those of skill in the art to recognize other members of the claimed genus of antidepressant response prediction biomarkers. Nor is there evidence that hsCRP, IL-1β, IL-6, leptin, and folate are representative of the genus of antidepressant response prediction biomarkers. Table 1 of Kim et al. (Brain, Behavior, and Immunity. 104: 65-73: Published: May 23, 2022) demonstrates that not all biomarkers predictive of 12- week remission are also predictive of 12-month remission and vice versa. Even instant Specification Table 2 demonstrates that not all potential biomarkers can be used to predict remission within 12 weeks. Thus, there is a high degree of unpredictability in the art.
When read with context, the statement of unpredictability of biomarker use in depression is regarding the use of any biomarker in the genus of possible biomarkers. It is noted the Kim et al., cited in the previous rejection under 35 U.S.C. 112(a), supports the use of hsCRP, IL-1β, IL-6, and leptin as biomarkers associated at 12-week remission.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KATHERINE ANN HOLTZMAN whose telephone number is (571)270-0252. The examiner can normally be reached Monday - Friday 7:30am - 5:00pm.
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/KATHERINE ANN HOLTZMAN/Examiner, Art Unit 1646
/JULIET C SWITZER/Primary Examiner, Art Unit 1682