Office Action 1: Non-Final Rejection (2024-05-20)
Rejection types: 101 - Patent-Eligible Subject Matter, 112 - Written Description/Enablement, Double Patenting

CLAIMS:
We claim:

1\. A method for predicting post-traumatic stress disorder (PTSD) in a subject comprising the steps of:
a. measuring the DNA methylation level of a CpG located on the minus strand of chromosome 17, at position 57187729, from DNA isolated from a sample collected from the subject;
b. identifying the genotype at the single nucleotide polymorphism (SNP), rs7208505, from DNA isolated from a sample collected from the subject; and
c. predicting PTSD in the subject using a linear model that utilizes the DNA methylation level, genotype at rs7280505, age and sex.

2\. The method of claim 1, wherein the linear model further utilizes a stress/anxiety metric.

3\. The method of claim 2, wherein the stress/anxiety metric comprises the results from a stress/anxiety questionnaire.

4\. The method of claim 2, wherein the stress/anxiety metric comprises salivary cortisol measurement from the subject.

5\. The method of claim 2, wherein the stress/anxiety metric comprises a biomarker of salivary cortisol measured from the subject.

6\. The method of claim 1, wherein the sample is a blood, serum, or saliva sample.

7\. A method for predicting PTSD in a subject comprising the steps of:
a. measuring the DNA methylation level of a CpG located on the minus strand of chromosome 17, at position 57187729, from DNA isolated from a sample collected from the
subject;
b. identifying the genotype at the single nucleotide polymorphism (SNP), rs7208505, from DNA isolated from a sample collected from the subject; and
c. predicting PTSD in the subject using a linear model that utilizes the DNA methylation level, genotype at rs7280505, age, sex and a stress/anxiety metric.
8\. The method of claim 7, wherein the stress/anxiety metric comprises the results from a stress/anxiety questionnaire.

9\. The method of claim 7, wherein the stress/anxiety metric comprises salivary cortisol measurement from the subject.

10\. The method of claim 7, wherein the stress/anxiety metric comprises a biomarker of salivary cortisol measured from the subject.

11\. The method of claim 7, wherein the sample is a blood, serum, or saliva sample.

12\. A method for predicting PTSD comprising the steps of:
a. measuring DNA methylation level at a CpG dinucleotide located in the 3'
untranslated region (UTR) of SKA2 from DNA isolated from a sample collected from the subject;
b. identifying the genotype at the SNP rs7208505, from DNA isolated from a sample collected from the subject; and
c. predicting PTSD in the subject using a linear model that incorporates the
measured DNA methylation level and genotype.

13\. The method of claim 12, wherein the CpG dinucleotide in the 3' UTR of SKA2 is located on the minus strand of chromosome 17, at position 57187729.

14\. The method of claim 12, wherein the linear model further utilizes age and sex as additive covariates.

15\. The method of claim 12, wherein the linear model further utilizes a stress/anxiety metric.

16\. The method of claim 15, wherein the stress/anxiety metric comprises the results from a stress/anxiety questionnaire.

17\. The method of claim 15, wherein the stress/anxiety metric comprises salivary cortisol measured from the subject or a biomarker thereof.
18\. The method of claim 12, wherein the sample is a blood, serum, or saliva sample.

19\. The method of claim 12, wherein the sample is a blood, serum, or saliva sample taken before a stressor and then again after a stressor

20\. The method of claim 12, wherein the difference in DNA methylation at SKA2 is modeled with rs7208505 as an additive covariate to predict PTSD risk. 65 66 67 5 10 15 20 25 30 35

OFFICE ACTION:
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 .
This action is in response to the papers filed June 29, 2021.  Currently, claims 21-29 are pending.
Priority
This application is a CON of 15/517,215 filed 09/18/2017, now PAT 11072828 which is a 371 of PCT/US2015/054194 and claims priority to provisional application 62/060,503 filed October 6, 2014.
Drawings
The drawings are acceptable.
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 21-29 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter.
35 U.S.C. § 101 requires that to be patent-eligible, an invention (1) must be directed to one of the four statutory categories, and (2) must not be wholly directed to subject matter encompassing a judicially recognized exception. M.P.E.P. § 2106. Regarding judicial exceptions, “[p]henomena of nature, though just discovered, mental processes, and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work.” Gottschalk v. Benson, 409 U.S. 63, 67 (1972); see also M.P.E.P. § 2106, part II.
Based upon consideration of the claims as a whole, as well as consideration of elements/steps recited in addition to the judicial exception, the present claims fail to meet the elements required for patent eligibility.
Step 1
The claimed invention is directed to a process.
Question 2A
The claims are taken to be directed to an abstract idea, a law of nature and a natural phenomenon.
Claim 1 is directed to “a method for treating PTSD in a subject comprising administering a PTSD treatment to a subject predicted to have PTSD” where predicting PTSD by measuring DNA methylation at a CpG located in 3’ UTR of SKA2, identifying the genotype at SNP rs7208505 and predicting PTSD using a linear model.
Claim 1 is directed to a process that involves the judicial exceptions of an abstract idea (i.e. using a linear model and predicting PTSD) and a law of nature/natural phenomenon (i.e., the natural correlation between DNA methylation and the genotype at SNP rs7208505 and risk of PTSD).
Here, Claim 1 requires performing the step of “measuring the DNA methylation level at a CpG in the 3’ UTR of SKA2 and identifying the genotype at SNP rs7208505 as using a linear model to predict PTSD.    The specification teaches that data was downloaded (see page 31, line 5).  Using a linear model to determine PTSD is an abstract idea. This judicial exception is of the type identified by the Courts as an abstract idea akin to the following cases: “the collection, analysis, and display of available information in a particular field” (.Electric Power Group (Fed. Cir. 2016)); “the broad concept of monitoring audit log data” (FairWarning IP LLC (Fed Cir 2016)); Improvement to computer-related technology (e.g., computer functionality) (Enfish LLC (Fed. Cir. 2016)); “specific improvements in computer technology which go beyond well-understood, routine, conventional activities” (BASCOM (Fed. Cir. 2016)); “the incorporation of claimed rules that 'improved [the] existing technological process' by allowing the automation of further tasks. (McRO Inc. (Fed. Cir. 2016)) and “classifying and storing digital images in an organized manner”
As summarized in FairWarning, the courts have explained that the realm of abstract ideas includes collecting information, including when limited to particular content. (.Electric Power (Fed. Cir. 2016) (collecting cases listed above)). The courts have also treated analyzing information by steps people go through in their minds, or by mathematical algorithms, without more, as essentially mental processes within the abstract-idea category. And the courts have found that merely presenting the results of abstract processes of collecting and analyzing information, without more (such as identifying a particular tool for presentation), is abstract as an ancillary part of such collection and analysis. Id. Here, the claims are directed to a combination of these abstract-idea categories. Specifically, the claims here are directed to the collection of methylation and genotype data, and the mathematical analysis of that data, without significantly more.
The claims also involve the judicial exception of a law of nature/natural phenomenon.  The claims are based on the correlation between DNA methylation at a CpG site in the 3’UTR of SKA2 and the genotype at SNP rs7208505 and risk of PTSD.  The claims require predicting PTSD using a linear model.  As in Prometheus, the relation itself is a natural phenomenon that exists apart from any human action.
Question 2A Prong II
The exception is not integrated into a practical application of the exception.  The claims do not recite any additional elements that integrate the exception into a practical application of the exception.  While the claim recites obtaining a sample and genotyping, this is not an integration of the exception into a practical application.  Instead, these elements are data gathering required to perform the method.
With respect to the limitation of “administering a PTSD treatment to a subject predicted to have PTSD” this is a mere statement of “apply it”.  MPEP 2106.04(d)(2)(a) provides treatments must be “particular” such that they do not encompass all applications of the judicial exception.  This administration step of “administering a PTSD treatment” is not particular and is instead merely instructions to “apply” the exception in a generic way.  Thus, the administration step does not integrate the predicting step into a practical application.
Thus, the claim is “directed to” the exception.
Question 2B
The second step of Alice involves determining whether the remaining elements, either in isolation or combination with the other non patent ineligible elements, are sufficient to “’transform the nature of the claim’ into a patent eligible application” Alice, 134 S. Ct. at 2355 (quoting Mayo, 132 S. Ct. at 1297).
The claims are not sufficiently defined to provide a method which is significantly more from a statement of a natural principle for at least these reasons:
The claims do not include applying the judicial exception, or by use of, a particular machine.  The claims do not tie the steps to a “particular machine and therefore do not meet the machine or transformation test on these grounds.  The use of machines generally does not impose a meaningful limit on claim scope.
The claims are not considered to recite any additional steps or elements that amount to significantly more than route in and conventional activity and the steps/elements in the claims do not add something “significantly more” so as to render the claim patent eligible.
The claims broadly recite steps for measuring the DNA methylation level at a CpG located at position 57187729 of chromosome 17 and the genotype at SNP rs7208505 are not considered to add something significantly more to the judicial exceptions because the step is recited at a high level of generality.  Methods of obtaining a nucleic acid sample and determining the presence of methylation level sand polymorphisms in the sample were well-known routine and conventional at the time the invention was made.  The claims also do not add a specific limitation other than what is well-understood, routine and conventional in the field.
Perlegen teaches analysis of the ss24087298 mutation (namely the rs7208505 mutation).  Perlegen teaches identifying the G/A mutation at rs7208505.  The A allele is the major allele found in 56-78% of the population (see the three populations analyzed).  Perlegen also provides the genotypes for each of the individuals.  For the individuals with the A/A genotype, no methylation would be present as the nucleotide cannot be methylated.
Mehta teaches investigating DNA methylation profiles of the transcripts differentially regulated in either the PTSD case groups versus controls using the Illumina 450K Human Methylation array.  The instant specification teaches that the CpG at 57187729 of chromosome 17 is located on the Illumina 450K Bead Chip.  Mehta teaches that the CpG at 57187729 of chromosome 17 is not differentially methylated (see Supplemental Table 1).  Thus, methylation level of the CpG in the PTSD cases, where the sex and age of the patients was known, and the controls were determined even though they were found to be unmethylated.  Since Mehta did not identify any methylation, the genotype at the SNP rs7208505 was inherently the wild-type T which is not methylated.   Mehta teaches trauma questionnaires were used to measure stress/anxieties including sexual, physical and emotional abuse, and emotional and physical neglect (page 8306).
The step of obtaining a nucleic acid sample and analyzing the nucleic acids in the sample to determining the methylation level and genotype are data gathering steps necessary to use the judicial exceptions.  It merely tells the users of the method to determine the methylation level and genotype of a sample without further specification as to how the sample should be analyzed.   The claim does not recite a new, innovative method for such determination.  The predicting step is also a data manipulation method.  As such, the steps constitute insignificant, pre-solution activity.  The steps merely instruct the practitioner to use any well-known, conventional technique with generic reagents to detect the methylation level and polymorphism.
With regard to the element of a linear model that utilizes the DNA methylation level, genotype, age and sex, this element is generically recited and is insufficient.  It does not amount to significantly more than the judicial exception(s).  As the courts have explained, the use of generic computer elements like a microprocessor or user interface do not alone transform an otherwise abstract idea into patent-eligible subject matter. See DDR Holdings (Fed. Cir. 2014).
Further, the Alice Corp decision informs in regards to method claims: Use of an unspecified, generic computer does not transform an abstract idea into a patent-eligible invention. Thus, the claim does not amount to significantly more than the abstract idea itself’. (Federal Register Vol. 79, No. 241, 74628 Tuesday, December 16, 2014).  Here, the claim is not specific to a computer but relies upon a generic linear model.  The instant claims recite only generic linear models in conventional use.  It may be impractical and tedious to analyze bioinformatics data without an electronic computer, but it is not impossible.
Further the courts have found that:
“Though that analysis can be difficult, it is facilitated somewhat if, as here, the only physical step involves merely gathering data for the algorithm. As stated in In re Christensen, 478 F.2d 1392. 1394. 178 USPO 35. 37-38 1CCPA 1973): “Given that the method of solving a mathematical equation may not be the subject of patent protection, it follows that the addition of the old and necessary antecedent steps of establishing values for the variables in the equation cannot convert the unpatentable method to patentable subject matter.” Accord; In re Chatfield, (CCPA 1976). The reason for this was explained in In re Sarkar. “No mathematical equation can be used, as a practical matter, without establishing and substituting values for the variables expressed therein. Substitution of values dictated by the formula has thus been viewed as a form of mathematical step. If the steps of gathering and substituting values were alone sufficient, every mathematical equation, formula, or algorithm having any practical use would be per se subject to patenting as a process under § 101. Consideration of whether the substitution of specific values is enough to convert the disembodied ideas present in the formula into an embodiment of those ideas, or into an application of the formula, is foreclosed by the current state of the law”, (as cited in In re Grams, 888 F.2d 835 (CAFC 1989 at 840).
The claims further suffer from not applying the abstract idea in a meaningful way. These claims are considered mathematical relationships/formulas that are not applied in a specific way so as to render the claims practically applied, (see Benson or Parker v. Flook). The claims manipulate data using well-known, conventional techniques without adding a patent eligible application. Further action must be taken upon the results of the generic “analysis” or “linear model”.
In summation, the limitations of the claims, individually, and in ordered combination as a whole, do not rise to the level of significantly more than the judicial exception(s) identified above, and the claims are not patent eligible subject matter.
Claim Rejections - 35 USC § 112-Scope of Enablement
The following is a quotation 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.
Claims 21-29 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 a method of measuring DNA methylation levels, detecting a genotype at SNP rs7208505, does not reasonably provide enablement for methods of predicting a subject has PTSD using a linear model that incorporates the measured DNA methylation level and genotype to predict PTSD in the subject.   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.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 USC 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (CA FC 1988).  Wands states at page 1404,
“Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex parte Forman. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.”
The nature of the invention and breadth of claims
Claims 21-29 are drawn to methods of predicting a subject has PTSD using a linear model that incorporates the measured DNA methylation level and genotype to predict PTSD in the subject.
The invention is in a class of invention which the CAFC has characterized as “the unpredictable arts such as chemistry and biology.”  Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001).
The unpredictability of the art and the state of the prior art
The art teaches analysis of methylation and genotypes in SAK2.  Perlegen teaches analysis of the ss24087298 mutation (namely the rs7208505 mutation).  Perlegen teaches identifying the G/A mutation at rs7208505.  The A allele is the major allele found in 56-78% of the population (see the three populations analyzed).  Perlegen also provides the genotypes for each of the individuals.  For the individuals with the A/A genotype, no methylation would be present as the nucleotide cannot be methylated.
Mehta teaches investigating DNA methylation profiles of the transcripts differentially regulated in either the PTSD case groups versus controls using the Illumina 450K Human Methylation array.  The instant specification teaches that the CpG at 57187729 of chromosome 17 is located on the Illumina 450K Bead Chip.  Mehta teaches that the CpG at 57187729 of chromosome 17 is not differentially methylated (see Supplemental Table 1).  Thus, methylation level of the CpG in the PTSD cases, where the sex and age of the patients was known, and the controls were determined even though they were found to be unmethylated.  Since Mehta did not identify any methylation, the genotype at the SNP rs7208505 was inherently the wild-type T which is not methylated.   Mehta teaches trauma questionnaires were used to measure stress/anxieties including sexual, physical and emotional abuse, and emotional and physical neglect (page 8306).
Guidance in the Specification.
The specification provides no evidence that the broad scope of the claims would enable the skilled artisan to practice the claimed invention as broadly as claimed.
The specification teaches methylation variation at rs7208505 represents the first genetic and epigenetic biomarker capable of predicting PTSD in a prospective manner with over 75% accuracy from blood (Page 29, lines 30-35).  The rs7208505 SNP and the cg13989295 are located at the same position in the genome such that the T/C variation is also measured for methylation of the variant C.
The specification analyzes and applies a suicide prediction model to PTSD.  The ability of the suicide prediction model to identify PTSD cases from the GTP cohort varied.  One model provided an AUC of 0.55 and p=0.24.  Another provided a significant value (see page 38).  Further an interactive model had a p-value of 0.066 (page 44).  Even more, no significant interactions were observed with the model with CTQ (see page 45).  Each model yielded different results and different significance.
Table 6 illustrates numerous CpG sites in the SKA2 region and their association with PTSD.  It is clear that only three of the 18 sites tested had a significant p-value association with methylation and PTSD.  Thus, it is unpredictable which DNA methylation levels in the 3’ UTR region of SKA2 may be used in the linear model to predict PTSD without further unpredictable and undue experimentation.
The guidance provided by the specification amounts to an invitation for the skilled artisan to try and follow the disclosed instructions to make and use the claimed invention.
Quantity of Experimentation
The quantity of experimentation in this area is extremely large since there is significant number of parameters which would have to be studied to enable the skilled artisan to predict PTSD in a subject using a linear model that incorporates any CpG dinucleotide methylation level from the 3’ UTR of SKA2 and genotype of rs7208505.  The evidence in the specification provides that only three of 18 studied CpG sites provide any significant association with PTSD.  The skilled artisan would be required to perform significant additional experimentation to determine which, if any CpG sites, aside from cg13989295 at the same position as rs7208505, would allow prediction of PTSD.
Further the specification does not provide a clear discussion of the linear model that would allow PTSD to be predicted.  The specification discusses numerous linear models, some that work and some that do not work to predict PTSD.  It is unpredictable what elements are required to be present to allow prediction of PTSD using DNA methylation and genotype analysis of rs7208505.
This would require significant inventive effort, with each of the many intervening steps, upon effective reduction to practice, not providing any guarantee of success in the succeeding steps.
Level of Skill in the Art
The level of skill in the art is deemed to be high.
Conclusion
Thus given the broad claims in an art whose nature is identified as unpredictable, the unpredictability of that art, the large quantity  of research required to define these unpredictable variables, the lack of guidance provided in the specification, the absence of a working example and the negative teachings in the prior art balanced only against the high skill level in the art, it is the position of the examiner that it would require undue experimentation for one of skill in the art to perform the method of the claim as broadly written.
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.
Claims 21-29 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.
Claim 21 requires administering a PTSD treatment to a subjected predicted to have PTSED and diagnosed as such.  It is unclear what diagnosed as such means and requires.  The claim sets forth a using a linear model to predict PTSD in a subject but provides no guidance or antecedent basis for diagnosis of PTSD.  It is unclear what more is required for diagnosis that is not required for predicted to have PTSD.  Thus, “diagnosed as such” lacks proper antecedent basis.  Claims 22-29 are similarly indefinite as they depend on Claim 21.
Claim 28 is indefinite over “the difference in DNA methylation” because “the difference” lacks proper antecedent basis.  Claim 21 does not provide any difference, comparison or relationship.  Thus, it is unclear what difference in DNA methylation at SKA2 is referred to.  Clarification is required.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the right to exclude granted by a patent and to prevent possible harassment by multiple assignees.  See In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970);and, In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the conflicting application or patent is shown to be commonly owned with this application.  See 37 CFR 1.130(b).
Effective January 1, 1994, a registered attorney or agent of record may sign a terminal disclaimer.  A terminal disclaimer signed by the assignee must fully comply with 37 CFR 3.73(b).
An obviousness-type double patenting rejection is appropriate where the conflicting claims are not identical, but an examined application claim is not patentably distinct from the reference claim(s) because the examined claim is either anticipated by or would have been obvious over, the reference claim(s).  See e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985).
Claims 21-29 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 7-13 of Patent 10,280,464 (reference application) in view of Khan, Arifulla (WO 2011/11927, September 29, 2011).
Although the conflicting claims are not identical, they are not patentable distinct from each other because Claims 21-29 of the instant application is generic to all that is recited in claims 1-5, 7-13 of Patent 10,280,464 (reference application).	The instant claims are generic to the three active method steps as required by claims in ‘464.  While the intended use of ‘464 is for suicide attempts and the instant claims are directed to PTSD, these two phenotypes are overlapping in scope.  Further, the active method steps do not require anything different.   The instant specification, repeatedly provides that a previously published SKA2 suicide prediction rule for PTSD resulted in a significant prediction of PTSD (see pages 43, page 59, lines 15-20, for example).
‘464 does not teach treating the patients predicted to have suicide.
However, Khan teaches suicide may be treated using antidepressants.
Therefore, it would have been prima facie obvious at the time the invention was made to have treated patients predicted to have PTSD or suicidal thoughts with well known treatments, as taught by Khan.  Therefore, the instant claims are obvious in view of the allowed claims in ‘464.
Claims 21-29 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of Patent 11,072,828 (reference application) in view of Helton et al. (WO 2009/062134, May 14, 2009).
Although the conflicting claims are not identical, they are not patentable distinct from each other because Claims 21-29 of the instant application is generic to all that is recited in claims 1-14 of Patent 11,072,828 (reference application).	The instant claims are generic to the three active method steps as required by claims in ‘828.
‘828 does not teach treating the patients predicted to have PTSD.
However, Helton teaches patients predicted to have PTSD or diagnosed with PTSD may be treated.  Helton teaches current treatment options for PTSD include patient education, social support, and anxiety management through psychotherapy and psychopharmacologic intervention. Helton also teaches medications for treating PTSD include antidepressants and antipsychotic drugs. Paroxetine (Paxil) and sertraline (Zoloft) are currently the only medications that have been approved by the U.S. Food and Drug Administration for the treatment of PTSD.
Therefore, it would have been prima facie obvious at the time the invention was made to have treated patients predicted to have PTSD with well known PTSD treatments, as taught by Helton.  Therefore, the instant claims are obvious in view of the allowed claims in ‘828.
Conclusion
No claims allowable.


NEXT OFFICE 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 .
Reasons for Allowance
The following is an examiner’s statement of reasons for allowance:
The claims are directed to measuring DNA methylation level of the CpG dinucleotide located on the minus strand of chromosome 17, at position 57187729 (cg13889295) and the genotype at the same position (rs7208505) and using a linear model to predict PTSD in the subject and administering a PTSD treatment to a subject predicted to have PTSD.  The claims have been amended to require a particular treatment for PTSD.
The specification teaches predicting PTSD in patients using the CpG dinucleotide located on the minus strand of chromosome 17, at position 57187729 (cg13889295) and the genotype at the same position (rs7208505)(para 102).  Figure 1 illustrates the area under the curve for the analysis is 0.78.
The Double Patenting rejection over Patent 10,280,464 has been withdrawn in view of the terminal disclaimer filed on November 20, 2024.
Any comments considered necessary by applicant must be submitted no later than the payment of the issue fee and, to avoid processing delays, should preferably accompany the issue fee.  Such submissions should be clearly labeled “Comments on Statement of Reasons for Allowance.”
Conclusion

CITED REFERENCE SUMMARIES: Ref US10280464B2: Claims:
A method for predicting suicide attempt and/or suicide ideation by a subject comprising the steps of: (a) measuring the DNA methylation level of a CpG located on the minus strand of chromosome 17, at position 57187729, from DNA isolated from a sample collected from the subject, wherein the DNA methylation level is measured using a primer comprising SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4 or SEQ ID NO:5; (b) detecting the genotype at the single nucleotide polymorphism (SNP), rs7208505, from DNA isolated from a sample collected from the subject; and (c) using a linear model that utilizes the DNA methylation level, genotype at rs7208505, age and sex to predict suicide attempt and/or suicide ideation by the subject.
(a) measuring the DNA methylation level of a CpG located on the minus strand of chromosome 17, at position 57187729, from DNA isolated from a sample collected from the subject, wherein the DNA methylation level is measured using a primer comprising SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4 or SEQ ID NO:5;
(b) detecting the genotype at the single nucleotide polymorphism (SNP), rs7208505, from DNA isolated from a sample collected from the subject; and
(c) using a linear model that utilizes the DNA methylation level, genotype at rs7208505, age and sex to predict suicide attempt and/or suicide ideation by the subject.
The method of claim 1 , wherein the linear model further utilizes a stress/anxiety metric.
The method of claim 2 , wherein the stress/anxiety metric comprises the results from a stress/anxiety questionnaire.
The method of claim 2 , wherein the stress/anxiety metric comprises salivary cortisol measurement from the subject.
The method of claim 2 , wherein the stress/anxiety metric comprises a biomarker of salivary cortisol measured from the subject.
The method of claim 5 , wherein the biomarker of salivary cortisol comprises CpG dinucleotide methylation at one or more of the following genes: EXOC4, KRT6A, MUC1, CLEC18B, MST1P2, ROMO1, MAPK1IP1L, HCRTR1, EPS15, DCHS2, FABP7, HOXC11, SLC26A1, DEXI, AMTN, PNPT1, SLC9A3, NOD2, CDH4, PLA2G7, BCAS3, RBBP5, FAM167A, YKT6, ANKH, CDH22, DGKI, CACNA1H, LRTOMT, SCARF2, KLHL29, MAP4K5, ATL1, MAP4K5, SLC29A4, C14orf180, NOB1, MRAP2, ZNF496, ANGPT1, ABCC8, PTPRN2, GPC5, RNF115, ZDHHC11, PCDHA6, PCDHA2, PCDHA1, PCDHA7, PCDHA1, PCDHA6, PCDHA5, PCDHA9, PCDHA9, PCDHA3, PCDHA4, PCDHA8, GABBR1, SDK1, CAMTA1, SKI, RPS6KC1, GALNT9, SPAG6, HIST2H2BF, SPINT3, KIAA0664, TSNARE1, EPS8L2, PICALM, BCL2L10, HTR3C, CNGA3, DERL1, COL23A1, BACE1, SRPK2, RNF111, SPATA7, FAM189A1, TRIM55, ARMC9, MTHFD1L, and SLC8A2.
EXOC4, KRT6A, MUC1, CLEC18B, MST1P2, ROMO1, MAPK1IP1L, HCRTR1, EPS15, DCHS2, FABP7, HOXC11, SLC26A1, DEXI, AMTN, PNPT1, SLC9A3, NOD2, CDH4, PLA2G7, BCAS3, RBBP5, FAM167A, YKT6, ANKH, CDH22, DGKI, CACNA1H, LRTOMT, SCARF2, KLHL29, MAP4K5, ATL1, MAP4K5, SLC29A4, C14orf180, NOB1, MRAP2, ZNF496, ANGPT1, ABCC8, PTPRN2, GPC5, RNF115, ZDHHC11, PCDHA6, PCDHA2, PCDHA1, PCDHA7, PCDHA1, PCDHA6, PCDHA5, PCDHA9, PCDHA9, PCDHA3, PCDHA4, PCDHA8, GABBR1, SDK1, CAMTA1, SKI, RPS6KC1, GALNT9, SPAG6, HIST2H2BF, SPINT3, KIAA0664, TSNARE1, EPS8L2, PICALM, BCL2L10, HTR3C, CNGA3, DERL1, COL23A1, BACE1, SRPK2, RNF111, SPATA7, FAM189A1, TRIM55, ARMC9, MTHFD1L, and SLC8A2.
The method of claim 1 , wherein the sample is a blood, serum, or saliva sample.
A method for predicting suicide ideation and/or suicide attempt comprising the steps of: (a) measuring DNA methylation level at a CpG dinucleotide located in the 3′ untranslated region (UTR) of SKA2 from DNA isolated from a sample collected from the subject, wherein the DNA methylation level is measured a primer comprising SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4 or SEQ ID NO:5; (b) detecting the genotype at the SNP rs7208505, from DNA isolated from a sample collected from the subject; and (c) using a linear model that incorporates the measured DNA methylation level and genotype to predict suicide attempt and/or suicide ideation.
(a) measuring DNA methylation level at a CpG dinucleotide located in the 3′ untranslated region (UTR) of SKA2 from DNA isolated from a sample collected from the subject, wherein the DNA methylation level is measured a primer comprising SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4 or SEQ ID NO:5;
(b) detecting the genotype at the SNP rs7208505, from DNA isolated from a sample collected from the subject; and
(c) using a linear model that incorporates the measured DNA methylation level and genotype to predict suicide attempt and/or suicide ideation.
The method of claim 8 , wherein the linear model further utilizes age and sex as additive covariates.
The method of claim 8 , wherein the linear model further utilizes a stress/anxiety metric.
The method of claim 10 , wherein the stress/anxiety metric comprises the results from a stress/anxiety questionnaire.
The method of claim 10 , wherein the stress/anxiety metric comprises salivary cortisol measured from the subject or a biomarker thereof.
The method of claim 8 , wherein the sample is a blood, serum, or saliva sample.
Ref US11072828B2: Claims:
A method for predicting post-traumatic stress disorder (PTSD) in a subject comprising the steps of: (a) measuring the DNA methylation level of a CpG located on the minus strand of chromosome 17, at position 57187729, from DNA isolated from a sample collected from the subject, wherein the DNA methylation level is measured using a primer comprising SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4 or SEQ ID NO:5; (b) detecting the genotype at the single nucleotide polymorphism (SNP), rs7208505, from DNA isolated from a sample collected from the subject; and (c) using a linear model that utilizes the DNA methylation level, genotype at rs7208505, age and sex to predict PTSD in the subject.
(a) measuring the DNA methylation level of a CpG located on the minus strand of chromosome 17, at position 57187729, from DNA isolated from a sample collected from the subject, wherein the DNA methylation level is measured using a primer comprising SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4 or SEQ ID NO:5;
(b) detecting the genotype at the single nucleotide polymorphism (SNP), rs7208505, from DNA isolated from a sample collected from the subject; and
(c) using a linear model that utilizes the DNA methylation level, genotype at rs7208505, age and sex to predict PTSD in the subject.
The method of claim 1 , wherein the linear model further utilizes a stress/anxiety metric.
The method of claim 2 , wherein the stress/anxiety metric comprises the results from a stress/anxiety questionnaire.
The method of claim 2 , wherein the stress/anxiety metric comprises salivary cortisol measurement from the subject.
The method of claim 2 , wherein the stress/anxiety metric comprises a biomarker of salivary cortisol measured from the subject.
The method of claim 1 , wherein the sample is a blood, serum, or saliva sample.
A method for predicting PTSD comprising the steps of: (a) measuring DNA methylation level at a CpG dinucleotide located in the 3′ untranslated region (UTR) of SKA2 from DNA isolated from a sample collected from the subject, wherein the DNA methylation level is measured using a primer comprising SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4 or SEQ ID NO:5; (b) detecting the genotype at the SNP rs7208505, from DNA isolated from a sample collected from the subject; and (c) using a linear model that incorporates the measured DNA methylation level and genotype to predict PTSD in the subject.
(a) measuring DNA methylation level at a CpG dinucleotide located in the 3′ untranslated region (UTR) of SKA2 from DNA isolated from a sample collected from the subject, wherein the DNA methylation level is measured using a primer comprising SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4 or SEQ ID NO:5;
(b) detecting the genotype at the SNP rs7208505, from DNA isolated from a sample collected from the subject; and
(c) using a linear model that incorporates the measured DNA methylation level and genotype to predict PTSD in the subject.
The method of claim 7 , wherein the linear model further utilizes age and sex as additive covariates.
The method of claim 7 , wherein the linear model further utilizes a stress/anxiety metric.
The method of claim 9 , wherein the stress/anxiety metric comprises the results from a stress/anxiety questionnaire.
The method of claim 9 , wherein the stress/anxiety metric comprises salivary cortisol measured from the subject or a biomarker thereof.
The method of claim 7 , wherein the sample is a blood, serum, or saliva sample.
The method of claim 7 , wherein the sample is a blood, serum, or saliva sample taken before a stressor and then again after a stressor.
The method of claim 7 , wherein the difference in DNA methylation at SKA2 is modeled with rs7208505 as an additive covariate to predict PTSD risk.
Ref WO2009062134A1: Claims:
A method of treating post-traumatic stress disorder or acute stress disorder, comprising the step of administering to a patient in need thereof a therapeutic dose of a pharmaceutical composition comprising a compound having the following formula:
(a) A 2 and A 3 are C or N;
(b) R 3 is hydrogen, alkyl, aralky, heteroaralkyl, alkenyl, aralkenyl, heteroaralkenyl, aryl, heteroaryl, or does not exist when A 3 is N;
(c) R 6 is hydrogen, alkyl, aralkyl, heteroaralkyl, aryl or heteroaryl;
(d) R Ï 1 is hydrogen unless R(, is alkyl, in which case R 6 ' is hydrogen or the same alkyl as R 6 ;
(e) L is a linker group; and
(f) B has the following formula:
(i) R2 is hydrogen, alkyl, hydroxy, halo, alkoxy, cyano, methylthio;
(ii) R3 is hydrogen, alkyl, hydroxy, methoxy, halo, alkoxy, perfluoroalkyl, nitro, amino, aminocarbonyl, aminosulfonyl;
(iii) R2 and R3 can be taken together to form a 5 or 6 member aromatic or non-aromatic ring, which can contain from 0 to 3 heteroatoms selected from the group of N, O, or S;  (iv) R 4 is hydrogen, alkyl, halo, alkoxy, perfluoroalkyl, perfluoroalkoxy, or nitro; and
(v) R 3 and R 4 when taken together can form a 5 or 6 membered ring and can contain one or more heteroatoms; and pharmaceutically acceptable salts and esters thereof.
The method of claim 1 , wherein R 6 and R 6 ' are both hydrogen.
The method of claim 1 , wherein R 2 is selected from the group consisting of hydrogen, halo, and alkoxy.
The method of claim 1 , wherein R 3 is selected from the group consisting of hydrogen, alkyl, halo, alkoxy, and perfluoroalkyl.
The method of claim 4, wherein R 3 is trifluoromethyl.
The method of claim 4, wherein R3 is halo.
The method of claim 1 , wherein R 4 is selected from the group consisting of alkyl, halo, alkoxy, and perfluoroalkyl.
The method of claim 1 , wherein R 2 and R 3 when taken together form a naphthalene ring.
The method of claim 1 , wherein R 3 an R 4 are halo.
The method of claim 1, wherein R 2 an R 4 are halo.
The method of claim 1 , wherein L is straight chain alkyl group of the formula - (CH 2 ) m -, and wherein m is an integer between 1 and 6.
The method of claim 1 , wherein the composition of claim 1 is selected from the group consisting of: l-{2-[4-(3-Chlorophenyl)piperazin-l-yl]ethyl }-l ,5,6,7-tetrahydroindol-4-one; l-{4-[4-(4-Huorophenyl)piperazin-l-yl]butyl }-l,5,6,7-tetrahydroindol-4-one;
- { 4-[4-(4-Bromophenyl)piperazin- 1 -yljbutyl } - 1 ,5,6,7-tetrahydroindol-4-one;
- { 4-[4-(3-Trifluoromethylphenyl)piperazin- 1 -yl]butyl } - 1 ,5,6,7-tetrahydroindol-4-one; l-{2-[4-(3-Trifluoromethylphenyl)piperazin-l-yl]ethyl}-l ,5,6,7-tetrahydroindol-4-one; l-{3-[4-(3-Chlorophenyl)piperazin-l-yl]propyl }-l,5,6,7-tetrahydroindol-4-one;
- { 3-[4-(3-Trifluoromethylphenyl)piperazin- 1 -yl]propyl } - 1 ,5,6,7-tetrahydroindol-4-one;
- { 4-[4-(3,4-dichlorophenyl)piperazin- 1 -yl]butyl } - 1 ,5,6,7-tetrahydroindol-4-one;
- { 4-[4-(3-Chloro-4-fluorophenyl)piperazin- 1 -yl]butyl } - 1 ,5,6,7-tetrahydroindol-4-one; l -{4-[4-(2,4-Dichlorophenyl)piperazin-l-yl]butyl }-l,5,6,7-tetrahydroindol-4-one; and l -{ 3-[4-(3,4-Dichlorophenyl)piperazin-l-yl]propyl }-l ,5,6,7-tetrahydroindol-4-one.
The method of claim 1 , wherein the composition comprises a pharmaceutically acceptable excipient.
The method of claim 1, wherein the therapeutic dose is administered by an administrative route selected from the group consisting of intravenous, oral, topical, intraperitoneal, intravesical, transdermal, nasal, rectal, vaginal, intramuscular, intradermal, subcutaneous and intrathecal routes.
The method of claim 1, wherein the therapeutic dose is in the range of 0.0001 mg/kg to 60 mg/kg.
The method of claim 15, wherein the therapeutic dose is in the range of 0.3 mg/kg to 10 mg/kg.
The method of claim 1 , wherein the condition being treated is post-traumatic stress disorder.
Use of a pharmaceutical composition for treating post-traumatic stress disorder or acute stress disorder, wherein the composition comprises a compound having the following formula:
(c) R O is hydrogen, alkyl, aralkyl, heteroaralkyl, aryl or heteroaryl;
(d) R 6 1 is hydrogen unless Re is alkyl, in which case R O ' is hydrogen or the same alkyl as Re;
Ref WO2011119227A2: Claims:
A method for reducing suicidality in a human subject suffering from a central nervous system (CNS) disorder comprising coordinately administering a CNS therapeutic agent in an amount effective to treat said CNS disorder, and lithium in an amount effective to reduce suicidality in said subject.
The method of claim 1 , wherein said CNS disorder is selected from a mood disorder, psychosis, or other mental illness
The method of claim 1 , wherein said CNS disorder is a depressive disorder
The method of claim 1 , wherein said depressive disorder is selected from mild depression (dysthymia), major depressive disorder, depressive disorder not otherwise specified (NOS), seasonal affective disorder, bipolar disorder, cyclothymic disorder, neurotic depression, atypical (reactive) depression, mood disorders induced by alcohol or drugs, and other mood disorders.
The method of claim 4, wherein said depressive disorder is a major depressive disorder (single incidence or recurrent, unipolar depression).
The method of claim 1 , wherein said CNS disorder is a bipolar or manic depressive disorder
The method of claim 1 , wherein said CNS disorder is bipolar I disorder or bipolar II disorder.
The method of claim 1 , wherein said CNS disorder is an anxiety disorder
The method of claim 8, wherein said anxiety disorder is selected from generalized anxiety disorder, anxiety disorder not otherwise specified (NOS), obsessive-compulsive disorder (OCD), stress disorders including post-traumatic stress disorder (PTSD), phobias, panic disorders, and anxiety disorders induced by alcohol or drugs.
The method of claim 1 , wherein said CNS disorder is an appetite or eating disorder.
1. The method of claim 10, wherein said appetite disorder is selected from bulimia nervosa, anorexia nervosa, obesity, and eating disorders not otherwise specified.
The method of claim 1 , wherein said CNS disorder is an addictive disorder.
The method of claim 12, wherein said addictive disorder is selected from alcohol-related addictive disorders, nicotine-related addictive disorders,
amphetamine-related addictive disorders, cannabis-related addictive disorders,  cocaine-related addictive disorders, hallucinogen use disorders, inhalant-related addictive disorders, and opioid-related addictive disorders.
The method of claim 1, wherein said CNS disorder is selected from psychotic disorders, Alzheimer's disease, Parkinson's disease, epilepsy, seizure disorders, tic disorders, attention deficit/hyperactivity disorders, learning disorders, impulse control disorders, oppositional defiant disorders, conduct disorders, abnormal sexual behaviors, schizoid behaviors, somatization, sleep disorders, autism spectrum disorders, and personality disorders.
The method of claim 14, wherein said psychotic disorder is selected from schizophrenia, schizophreniform diseases, acute mania, schizoaffective disorders, and depression with psychotic features.
The method of claim 1 , wherein said CNS therapeutic agent is selected from anti-depressant, anxiolytic, anticonvulsant, antipsychotic, anti-addictive, and appetite suppressant drugs.
The method of claim 1 , wherein the CNS therapeutic agent is an antidepressant drug.
The method of claim 17, wherein the anti-depressant drug is selected from tricyclic anti-depressants (TCAs), specific monoamine reuptake inhibitors, selective serotonin reuptake inhibitors (SSRJs), selective norepinephrine reuptake inhibitors, selective dopamine reuptake inhibitors, multiple monoamine reuptake inhibitors, monoamine oxidase inhibitors (MAOIs), and indeterminate (atypical) antidepressants.
The method of claim 17, wherein the anti-depressant drug is an SSRI.
The method of claim 19, wherein the SSRI is selected from citalopram, excitalopram oxalate, fluvoxamine, paroxetine, fluoxetine, and sertraline.
The method of claim 1 , wherein the CNS therapeutic agent is citalopram.
The method of claim 17, wherein the anti-depressant agent is a tricyclic antidepressant (TCA).
The method of claim 22, wherein the TCA is selected from doxepin, clomipramine, amitriptyline, amitriptyline, maprotiline, desipramine, nortryptyline, desipramine, doxepin, trimipramine, imipramine, and protriptyline.
The method of claim 17, wherein the anti-depressant drug is a monoamine oxidase inhibitor (MAOI).
The method of claim 22, wherein the MAOI is selected from phenelzine, nortriptyline, selegiline and tranylcypromine.
The method of claim 1 , wherein the CNS therapeutic agent is administered by a mode of delivery selected from oral, buccal, nasal, aerosol, topical, transdermal, mucosal, or injectable delivery.
The method of claim 26, Wherein the CNS therapeutic agent is delivered orally.
The method of claim 26, Wherein the CNS therapeutic agent is administered intravenously.
The method of claim 1 , wherein the CNS therapeutic agent is administered in a sustained release formulation.
The method of claim 29, wherein the sustained release formulation provides therapeutically effective plasma levels of said CNS therapeutic agent over a sustained delivery period of approximately 8 hours or longer.
The method of claim 29, wherein the sustained release formulation provides therapeutically effective plasma levels of said CNS therapeutic agent over a sustained delivery period of approximately 18 hours or longer.
The method of claim 29, wherein the sustained release formulation is a sustained release, oral, transdermal, or injectable formulation.
The method of claim 29, wherein the sustained release formulation comprises the CNS therapeutic agent combined with any one or combination of a drug-releasing polymer, matrix, bead, microcapsule, or other solid drug-releasing vehicle, a drug- releasing tiny timed-release pill or mini-tablet; a compressed solid drug delivery vehicle; a controlled release binder; a multi-layer tablet or other multi-layer or multi- component dosage form; a drug-releasing lipid; and a drug-releasing wax.
The method of claim 29, wherein the CNS therapeutic agent is administered in a dosage of from about 60 mg to about 1000 mg.
The method of claim 29, wherein the CNS therapeutic agent is administered in a once daily dosage form effective to alleviate said CNS disorder.
The method of claim 1 , wherein the CNS therapeutic agent is citalopram administered in an oral dosage of from about 20 mg to about 1000 mg effective to treat a depressive disorder in said subject.
The method of claim 1 , wherein the CNS therapeutic agent is citalopram administered in a sustained release formulation.
The method of claim 1, wherein the CNS therapeutic agent is an anxiolytic drug.
The method of claim 1 , wherein the CNS therapeutic agent is an
anticonvulsant drug.
The method of claim 1 , wherein the CNS therapeutic agent is an addiction suppressive drug.
The method of claim 1 , wherein the CNS 
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