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 .
Applicants' arguments, filed June 8, 2026, have been fully considered but they are not deemed to be fully persuasive. The following rejections and/or objections constitute the complete set presently being applied to the instant application.
In view of the amendments to the claims, new prior art rejections are set forth below that utilize the previously applied prior art references and a new reference to render the amended claims obvious.
Priority
The benefit claim has been reviewed in light of the amendments to the claimed. As set forth in greater detail below, the claims as currently presented contain new matter that is not supported by the disclosure of this or prior filed applications and therefore the claims still do not satisfy all the necessary conditions for the benefit of a filing date of an earlier filed application.
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, 3, 8, 9 and 20 were rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more. This rejection is MAINTAINED for the reasons of record set forth in the Office Action mailed March 6, 2026 and those set forth herein.
Applicants traverse this rejection on the grounds that the comparison step has been removed from claim 1 and thus there is no mental comparison step recited in the claims.
These arguments are unpersuasive. While the physical comparison step has been removed from the claim, the claim is drawn to the mental assessment of toxicity as recited in the preamble of the claim which requires a mental step. Administration of a drug to a subject is required to make sure an assessment to carry out assessment so the claims are still drawn to ineligible subject matter.
Claim Rejections - 35 USC § 112 – New Matter
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 3, 8, 9 and 20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
The new language at the end of claim 1 defines the control measurement as being “a GFAP [glial fibrillary acidic protein] measurement obtained from a sample prior to the individual being exposed to the drug”. The Examiner was unable to locate any disclosure of this temporal linkage between the control sample and the individual being exposed to the drug. The claim does not require the control sample to come from the individual being assessed for cellular toxicity and any sample can form the basis for the control measurement. ¶¶ [0017] and [0018] of the PGPub of the instant application discuss the definition of the control and samples from healthy individuals or typical values given by assay manufacturers can be the control measurement or value. ¶ [0018] does state “[a]lternatively, the control value is a value taken from an in vitro sample of the same individual when classified as healthy” but the claim does not use the term healthy but rather “prior to the individual being exposed to the drug”. In the time frame as claimed, the subject can be unhealthy but not yet exposed to the drug and that would qualify as the control, and that is not covered by the alternative situation.
If Applicant is in disagreement with the Examiner regarding support for the amended claim, Applicant is respectfully requested to point to page and line number wherein support may be found for the instant invention.
Claim Rejections - 35 USC § 112 - Indefiniteness
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 3, 8, 9, and 20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 has been amended to delete any transitional words, language or punctuation after the preamble of “[a] method of assessing cellular toxicity of a drug”. In addition to not being grammatically correct, it is now unclear if the claims are open or closed to the presence of additional unrecited steps in the absence of such transitions.
Claim 1 recites the limitation "the individual" in lines 4 and 10. There is insufficient antecedent basis for this limitation in the claim.
The phrase “a sample” appears in both lines 3 and 10 and this along with lack of antecedent basis for “the individual” and the phrasing of the claim make the basis for the control measurement unclear. Line 7 recites “the sample” with no additional language but when read overall the claim contains two recitations of “a sample”. Do both samples need to be the same type of sample with the only relevant information being the time of sample collection as the sample in the control measurement must occur prior to the individual being exposed to the drug?
The dependent claims fall therewith.
Please clarify.
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.
Claim(s) 1, 3, 8, 9 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Cookson et al. (Toxic in Vitro, 1994) in view of Gorman et al. (J Clin Psychiatry, 1999) further in view of Mayer et al. (PloS One, 2013)
Cookson et al. discloses culturing of astrocytes (p 352, col 1, ¶ 2), which reads on an in vitro cell line or cell model. Sterile dilution of the test compounds were made in culture media and cultures were exposed to toxicants for 24 hours (p 352, col 1, ¶ 3), reading on administering a drug to an in vitro cell line or cell model. GFAp was then measured by ELISA (enzyme-linked immunosorbent assay; p 352, col 2, ¶ 2). The amount of antigen was compared to untreated wells (p 352, col 2, ¶ 2), which would generate a control measurement and such a control measurement takes place prior to administering the drug as no drug is ever administered. As shown in Table 1, a calculation of the increase would require comparison with the control measurement. See also the legend of figure 1 which states that each point is expressed as a percentage of the control (untreated) well. An excellent correspondence between compounds thought to be toxic to astrocytes and those that increased GFAp expression suggests that GFAp increases are an unequivocal marker for astrocyte damage (p 358, col 2, ¶ 5).
The screening of SSRIs is not specifically disclosed.
Gorman et al. discloses that SSRIs and serotonin/norepinephrine reuptake inhibitors (SNRIs) have proven effective in the treatment of major depression (p 33, col 1, ¶ 1).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to use the assay of Cookson et al. to screen for effects of SSRIs on GFAP content in primary astrocyte cultures. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because the method of Cookson et al. can be used to provide information about toxicity of brain cells which could be of particular relevance for drugs such as SSRIs whose site of action is the brain.
The collection of a sample as in claim 20 from a subject are not disclosed by either reference.
Mayer et al. discloses that GFAP has been identified as a potential blood biomarker for intercerebral hemorrhage in patients with symptoms of acute stroke (p 1, col 1) with blood levels of this highly specific brain protein in health individuals typically being low and not exceeding the lower detection limits of tests used (p 1, col 2). Little is known about GFAP release in other neurological disorders so blood samples were collected and GFAP plasma levels determined (whole document, e.g., abstract).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to use a blood sample to measure GFAP levels as disclosed by Mayer et al. to measure GFAP levels in subjects taking drugs such as SSRIs that act in the brain to assay for potential toxicity. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because Mayer et al. discloses that blood samples are a suitable means by which GFAP can be measured. These teachings, along with the teachings of neurotoxic substances can cause increases in GFAP levels means that one of ordinary skill in the art would have a reasonable expectation that changes in GFAP levels, should they occur, could be detected in subjects using a blood sample.
"A 'whereby' clause that merely states the result of the limitations in the claim adds nothing to the patentability or substance of the claim." Texas Instruments, Inc. v. International Trade Comm., 988 F.2d 1165, 1172 (Fed. Cir. 1993). See also Minton v. National Assoc. of Securities Dealers, Inc., 336 F.3d 1373, 1381 (Fed. Cir. 2003) ("A whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.") MPEP 2111.04
The wherein clause of claim 1 merely characterizes the results of those measuring step. Therefore, we determine that the "wherein" clause is not entitled to weight in construing the claim.
Regarding the previously applied references used in the new grounds of rejection above, Applicants argue that as GFAP is a marker for neurotoxicants and the skilled person would have no reason to expect that therapeutics such as SSRIs would produce a similar increase in GFAP merely because they act on the CNS (central nervous system). Cookson does not teach SSRIs. Gorman relates to the clinical efficacy of SSRIs and concludes they are safe and well tolerated for teaching psychiatric illnesses, that is not reason to believe that SSRIs would have adverse effects worth investigating, let alone the link to SSRIs.
These arguments are unpersuasive. Cookson et al. discloses at the end of the abstract and end of the articles that astrocytes have a valuable place in culture models for neurotoxicity. The instant methods do not require a reasonable expectation that increases in GFAP would occur upon exposure to a SSRU. The claims are rendered obvious by the motivation of one of ordinary skill to screen compounds like SSRIs that are routinely administered to subjects for possible toxicities, including by acting on astrocytes that can be assayed using a blood test. The abstract of Gorman et al. notes that these drugs “lack most of the adverse side effects of tricyclic antidepressants and monoamine oxidase inhibitors”. Even drugs that are considered safe can still exhibit side effects in some patients. But given the overall safety profile, assaying for altered GFAP levels in a subject can be ethically carried out to provide an indicator of astrocyte toxicity for these drugs that may not be noticeable to a subject or confirmation that astrocyte toxicity is not an issue for the particular drug being tested in the most relevant model rather than an in vitro tissue culture model as in Cookson et al.
Claim(s) 1, 3, 8, 9 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Cho et al. (Human Mol Genetics, 2010) in view of Gorman et al. (J Clin Psychiatry, 1999) further in view of Mayer et al. (PLos One, 2013).
Cho et al. discloses screening for compounds that suppress GFAP expression (whole document, e.g., title). Primary astrocytes were cultured (p 3175, col 1, ¶ 2), reading on an in vitro cell line or cell model. Candidate drugs and compounds for screening and were present in solution (p 3175, col 2, ¶ 1) and 80 compounds were screened per 96 well plate with columns reserved as controls including astrocytes grown in the absence of any compound (p 3175, col 2, ¶ 2), the latter generating a control measurement that takes place prior to administering the drug as no drug/candidate compound is ever administered. The antidepressant clomipramine, selected because of its high ranking in the cell culture assay and ability to cross the blood brain barrier, was also administered to mice and GFAP promoter activity and protein measurements were carried out (p 3171, col 2 and p 3176, col 2, ¶ 3). Identifying compounds that decrease GFAP promoter activity and/or reduce GFAP protein levels (e.g., p 3170, col 1, ¶ 3) requires comparison with a control measurement. Cho et al. does not explicitly describe increased GFAP as being indicative of cellular toxicity but the method steps of the instant claims, administering a drug, measuring the amount of GFAP in a sample and comparing the measure amount of GFAP to a control measurement are the active steps required by the instant claims. A mental process of drawing a conclusion based on a particular change is not required for Cho et al. to anticipate the instant claims.
The screening of SSRIs is not specifically disclosed.
Gorman et al. is discussed above.
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to use the assay of Cho et al. to screen for effects of SSRIs on GFAP content in primary astrocyte cultures. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because information about the effect of SSRIs on GFAP levels could provide information regarding the etiology and treatment of depression.
The collection of a sample as in claim 20 from a subject are not disclosed by either reference.
Mayer et al. is discussed above.
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to use a blood sample to measure GFAP levels as disclosed by Mayer et al. to measure GFAP levels in subjects taking drugs already approved by the FDA such as SSRIs for any changes in GFAP levels. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because Mayer et al. discloses that blood samples are a suitable means by which GFAP can be measured. The purpose of Cho et al. is to screen compounds for such an effect any changes in GFAP levels that would occur could be detected in subjects using a blood sample.
"A 'whereby' clause that merely states the result of the limitations in the claim adds nothing to the patentability or substance of the claim." Texas Instruments, Inc. v. International Trade Comm., 988 F.2d 1165, 1172 (Fed. Cir. 1993). See also Minton v. National Assoc. of Securities Dealers, Inc., 336 F.3d 1373, 1381 (Fed. Cir. 2003) ("A whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.") MPEP 2111.04
The wherein clause of claim 1 merely characterizes the results of those measuring step. Therefore, we determine that the "wherein" clause is not entitled to weight in construing the claim.
Regarding the previously applied references used in the new grounds of rejection above, Applicants argue that Cho is directed to screening for suppressors of GFAP expression so the skilled person has no incentive to consider that an antidepressant such as an SSRI could elevate GFAP levels in some patients. The inventors have found that GFAP levels serve as a robust protein biomarker of cellular toxicity including whether a patient taking a SSRI is experiencing brain cell damage as a result of the drug. The specification as filed presents evidence in the context of PTSD patients with elevated GFAP levels compared to healthy individuals and those taking a SSRI had significantly higher GFAP levels than those not taking a SSRI.
These arguments are unpersuasive. The active step of the instant claims is measurement of GFAP levels in a any subject after exposure to a SSRI, which reads on a single administration for the purposes of looking for effects on GFAP expression. While Cho et al. was looking to screen compounds that have been already approved for human use by the FDA, a group of drugs which includes SSRIs, for decreased GFAP expression, that requires administration of the drug and assessment of GFAP levels. The expectation as to the results of SSRI exposure on GFAP expression levels is not required to be render the claims obvious. That GFAP is a biomarker for astrocyte toxicity as taught by Cookson et al. and Applicants do not establish a nexus between the referenced data from the specification and the instant claim is which a measurement of GFAP is made after exposure of a subject, even just once, of a SSRI.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Nissa M Westerberg whose telephone number is (571)270-3532. The examiner can normally be reached M - F 8 am - 4 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Michael Hartley can be reached at 571-272-0616. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Nissa M Westerberg/Primary Examiner, Art Unit 1618
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