DETAILED CORRESPONDENCE
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 September 25, 2025. Currently, claims 1-5, 7-38 are pending. Claims 33-38 have been withdrawn as drawn to non-elected subject matter.
Election/Restrictions
Applicant's election without traverse of Group I, Claims 1-5, 7-32 in the paper filed September 25, 2025 is acknowledged.
Claims 33-38 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.
The requirement is still deemed proper and is therefore made FINAL.
Priority
This application claims priority to
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Drawings
The drawings are acceptable.
Claim Objections
It is noted that there is no Claim 6 in the set of claims filed September 14, 2022. 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 1-5, 7-32 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.
Question 1
The claimed invention is directed to a process that involves a natural principle and a judicial exception.
Question 2A Prong I
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 diagnosing bipolar disorder” by measuring activity of the promoter of CPG2 “wherein the subject is selected as having bipolar disorder or being at risk of bipolar disorder when the activity of the CPG2 promoter is less than that of a control CPG2 promoter or fragment thereof”.
Claim 1 is directed to a process that involves the judicial exceptions of an abstract idea (i.e. the abstract steps of “diagnosing bipolar disease in a subject”, selecting the subject as having bipolar disorder” and the comparison to a control) and a law of nature/natural phenomenon (i.e. the natural correlation between the activity of the promoter of CPG2 and bipolar disorder).
Claim 2 further comprises the judicial exception of assessing the effect of an active agent upon activity of the CPG2 promoter and relies upon a comparison.
Claim 11 further comprises a method of identifying a SNP within the CpG 2 promoter associated with bipolar disorder. This identifying is a mental step that may be performed by merely reading a report and a law of nature that the SNP is associated with bipolar disease.
Claim 18 is directed to selecting the one or more active agents. The selection of an active agent is a mental step and does not require any actual administration or treatment of the patient. The claim only requires an active agent is selected.
Claim 22 is directed to selecting a subject for treatment. The selection of a subject for treatment is a mental step and does not require any actual administration or treatment of the patient. The claim only requires a patient is selected.
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons that follow.
Herein, the claims involve the patent-ineligible concept of an abstract process. For example, Claim 1 requires performing the step of “the subject is selected”. Neither the specification nor the claims set forth a limiting definition for "selected" and the claims do not set forth how “selection” is accomplished. As broadly recited the determining step may be accomplished mentally by thinking about a subject’s promoter activity level and mentally selecting the subject. The claim also requires “diagnosing” bipolar disease but does not set forth a limiting definition of diagnosing. The diagnosing may be simply performed mentally. Thus, these steps constitute an abstract process idea.
Claim 1 further recites a comparison between the activity of the promoter and a control that is deemed an abstract idea (see MPEP 2106.04(a)(2)(III)(A); • claims to “comparing BRCA sequences and determining the existence of alterations,” where the claims cover any way of comparing BRCA sequences such that the comparison steps can practically be performed in the human mind, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 763, 113 USPQ2d 1241, 1246 (Fed. Cir. 2014)). Claim 2 is also directed to a comparison step.
A correlation that preexists in the human is an unpatentable phenomenon. The association between activity levels in CPG2 and risk of bipolar disease is a law of nature/natural phenomenon. The "selecting” and “diagnosing" step which tells users of the process to predict bipolar disease in the sample, amounts to no more than an "instruction to apply the natural law". These steps are no more than a mental step. Even if the step requires something more such as to verbalize the discovery of the natural law, this mere verbalization is not an application of the law of nature to a new and useful end. The "selecting” and “diagnosing" step does not require the process user to do anything in light of the correlation. The "selecting” and “diagnosing" step fails to provide the “practical assurance” sought by the Prometheus Court that the “process is more than a drafting effort designed to monopolize the law of nature itself.”
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 measuring the activity of the promoter of CPG2, this is not an integration of the exception into a practical application. Instead, these elements are data gathering required to perform the method. Thus, the claim is “directed to” the exception.
Claim 21 recites treating the subject by administering an affective amount of the active agent, however, as noted in the 112B below, the claim is directed to treating all subject and is not an integration of a judicial exception.
Accordingly, the claims are directed to judicial exceptions.
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 also do not add a specific limitation other than what is well-understood, routine and conventional in the field. The measuring the activity of the promoter of CPG2 is mere data gathering step that amounts to extra solution activity to the judicial exception. It merely tells the users of the method to determine the activity of the promoter without further specification as to how the sample should be analyzed. The claim does not recite a new, innovative method for such determination. The determining step essentially tells users to determine the activity of the promoter through whatever known processes they wish to use.
The step of measuring activity of the promoter of CPG2 was well known in the art at the time the invention was made. The art teaches measuring activity of the promoter of CPG2 (see Sharp, 2018 and Rathje, 2019). The claim does not require the use of any particular non-conventional reagents. When recited at this high level of generality, there is no meaningful limitation that distinguishes this step from well understood, routine and conventional activities engaged in by scientists prior to applicant’s invention and at the time the application was filed.
Further it is noted that the courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity.
Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546;
Amplifying and sequencing nucleic acid sequences, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014)
For these reasons the claims are rejected under section 101 as being directed to non-statutory subject matter.
Claim Rejections - 35 USC § 112-Description
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 1-5, 7-32 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims are broadly drawn to methods which measure the activity of the promoter of CPG2 or a fragment of the promoter of CPG2 comprising a nucleic acid sequence between about 800bp and about 600bp upstream of the transcription start site of CPG2 which possess the functionality of being associated with bipolar disease.
Relevant to the lack of particular structural limitations in the rejected claims drawn to nucleic acids, MPEP 2163 states:
The claimed invention as a whole may not be adequately described if the claims require an essential or critical feature which is not adequately described in the specification and which is not conventional in the art or known to one of ordinary skill in the art.
Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 94 USPQ 2d 1161 (Fed. Cir. 2010) recently re-affirmed the written description requirement. Ariad reiterates that “the hallmark of written description is disclosure" and “possession as shown in the disclosure” is a more complete formulation of the test for written description. Ariad considers situations of genus claims and states that the written description requirement ensure that "when a patent claims a genus by its function or result, the specification recites sufficient materials to accomplish that function."
Vas-Cath Inc. V. Mahurkar, 19 USPQ2b 1111, clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed”. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 USC 112 is severable from its enablement provision. In The Regents of the University of California v. Eli Lilly (43 USPQ2b 1398-1412), the court held that a generic statement which defines a genus of nucleic acids by only their functional activity does not provide an adequate written description of the genus. The court indicated that while Applicants are not required to disclose every species encompassed by a genus, the description of a genus is achieved by the recitation of a representative number of DNA molecules, usually defined by a nucleotide sequence, falling within the scope of the claimed genus. At section B(1), the court states that “An adequate written description of a DNA…’ required a precise definition, such as by structure, formula, chemical name, or physical properties’, not a mere wish or plan for obtaining the claimed chemical invention”.
In the case of the instant claims, the functionality of identifying CPG2 promoter and fragments thereof diagnostic of bipolar or risk of bipolar disorder is a critical feature of the claimed methods.
The claims are directed to the CpG2 promoter. The claims are also directed to fragments of the promoter comprising a nucleic acid sequence about 800-600bp upstream of the transcription site. Claim 7 is directed to the fragment comprises from 1-800bp upstream of the transcription start site of CPG2 and claim 8 is directed to a fragment 1-1000bp upstream of the start site.
The specification teaches identifying several variants and polymorphisms in the TREX1 gene. However, it is not clear that all of these polymorphisms are associated with LE, as some were found in controls (see table 1; page 9). The specification teaches analyzing several CPG2 promoter regions using a dual-Luciferase reporter assay for promoter activity, the -1.0kb, -0.8kb, -0.6bk, -0.4kb, -0.2kb, -0.2kb i16 and 5’UTRi16 fragments.
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The specification teaches -0.8bk CPG2 promoter region, but not other regions are responsive to lithium treatment (page 49, line 30-31). The specification does not teach how different fragments of the promoter of CPG2 affect the activity of the promoter or how they are functionally associated with bipolar disorder.
It is clear from the art of Rathje et al (Mol. Psychiatry, Vol 26, No. 2, pages 508-523, July 19, 2019) that some promoter regions of CPG2 are to have decreased activity in bipolar disease. However, neither the specification nor the art teaches which fragments, the length of the fragments or the why if other fragments are associated with bipolar disease.
Given the guidance in the specification and what was taught in the art prior to the invention, the skilled artisan would be unable to predictably correlate structural changes of the promoter of CPG2 and the activity level and association with bipolar disorder, simply based on their existence.
The general knowledge and level of skill in the art do not supplement the omitted description because specific, not general guidance is what is needed. Since the disclosure fails to describe the common attributes or characteristics that identify members of the genus, and because the genus is highly variant, fragments of the promoter of CPG2 alone is insufficient to describe the genus of CPG2 promoter regions associated with bipolar disorder. The specification teaches not all fragments or regions of the promoter are associated similarly. There is no description of the fragments of CPG2 promoter that would and would not be associated with bipolar disorder. The specification provides no correlation between structure of the CPG2 promoter and fragments and the function of such fragments. One of skill in the art would conclude that applicant was not in possession of the claimed genus because a description of only one member of this genus is not representative of the variants of the genus and is insufficient to support the claim.
Thus, considering the breadth of the polynucleotides required by the claimed methods, their specific required functionalities, and the teachings of the instant specification, it is the conclusion that the specification does not provide an adequate written description of the broadly claimed subject matter.
Claims 18-19, 21, 22-25, 27 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims are broadly drawn to methods which select one or more active agents as a potential therapeutic agent which possess the functionality of increases the activity of the CPG2 promoter, or fragment thereof. The specification provides analysis of a single active agent, namely lithium treatment to test for the impact of lithium treatment on CPG2 transcription (page 50). The specification teaches that the -0.8bk CPG2 promoter region but no other region is responsive to lithium treatment (see Figure 3). The specification does not describe any other active agents that would increase the activity of the CPG2 promoter. The art does not describe other active agents that increase the activity of CPG2. The disclosure of a single active agent that increases the activity of CPG2 is not description of a representative number of members of the genus.
Claim Rejections - 35 USC § 112- Second Paragraph
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 1-5, 7-32 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 pre-AIA the applicant regards as the invention.
Claim 1 is directed to fragments of the promoter comprising a nucleic acid sequence about 800-600bp upstream of the transcription site. Claim 7 is directed to the fragment comprises from 1-800bp upstream of the transcription start site of CPG2 and claim 8 is directed to a fragment 1-1000bp upstream of the start site. It is unclear whether the claims are directed to particular locations of the promoter fragment or whether the claims are directed to lengths of the fragments. It is unclear how a claim to 1-800bp and 1-1000bp further limit a claim to 600-800bp upstream. The claims do not clearly set for the metes and bounds. Even more, the claims use the comprising transition so, the claims are not limited to any particular fragment but encompass larger sequences including the fragment. The dependent claims are similarly indefinite. Clarification is required.
Claim 21 is indefinite over the recitation “treating the subject”. It is unclear what subject is being treat. It is unclear whether all subjects tested are treated or whether a subject having bipolar disorder or a risk of bipolar disorder is treated. “The subject” lacks proper antecedent basis. Correction is required.
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.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Claim(s) 1-5, 7-17, 28-32 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Rathje et al (Mol. Psychiatry, Vol 26, No. 2, pages 508-523, July 19, 2019).
Rathje teaches genetic variants in the bipolar disorder risk locus SYNE1 that affect CPG2 expression and protein function. Rathje teaches identifying genetic variants within postmortem brains that map to CPG2 promoter region and show negatively affect gene expression (abstract). CPG2 protein levels are significantly decreased in postmortem brain tissue of bipolar disorder patients as compared to schizophrenia, depression and control subjects (page 3, para 2). The CPG2 region also contains genetic variants within promoter and enhancer regions that negatively affect gene expression. Figure 3 illustrates the -0.8kb region comprises an enhancer that negatively affects gene expression. Therefore, Rathje teaches a method of measuring the activity of the promoter and fragments from CPG2 that is indicative of decreased expression and bipolar disorder.
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With respect to Claims 2-4, 15-17, Rathje teaches performing molecular cloning and luciferase assays. The molecular cloning assays take PCR products from promoter regions that were separated on gels, excised, purified and cloned in a vector in front of the Firefly Luciferase gene. The reporter protein was expressed and quantified (see page 4-5).
With respect to Claim 5, Rathje teaches the fragment of the CPG2 promoter comprises about 200bp, namely the -0.8bk fragment with the highest luciferase activity.
With respect to Claim 7-8, the promoter is in the regions 0- 1.2kb upstream of the transcription site.
With respect to Claim 9-13, Rathje teaches analysis of SNP alleles, namely rs924872285 and rs4523096 that are identified in a biopolar disorder subject (see Figure 3 above).
With respect to Claim 14, the report protein is expressed in cultured cortical neuron cells (page 5, line 1).
With respect to Claim 28-32, the supplemental data provides information on the characteristics of the patients. The patients are all from known tissue banks and have schizophrenia, bipolar, controls or depression. The tissue bank information provides further characteristics of the subjects.
Conclusion
No claims allowable.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Sharp et al. (Psychiatr Genet, Vol. 27, No. 3, pages 81-88, June 2017) teaches rare non-synonymous variants in SYNE1/CPGS2 in bipolar affective disorder. Shart teaches screening two regions of increased transcriptional activity, including a CPG2 promoter region and genotyping rs148346599 in BPD and controls. The rs148346599 SNP is within the promoter region of the instant claims.
Loebrich et al. (Molecular and Cellular Neuroscience, Vol. 71, pages 46-55, 2016) teaches genomic mapping and cellular expression of human CPG2 transcripts in the SYNE1 gene. Loebrich does not teach analysis of promoter regions and the association with bipolar disorder.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JEANINE ANNE GOLDBERG whose telephone number is (571)272-0743. The examiner can normally be reached Monday-Friday 6am-3:30pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu-Cheng Winston Shen can be reached on (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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/JEANINE A GOLDBERG/Primary Examiner, Art Unit 1682
December 9, 2025