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 .
Election/Restrictions
Applicant’s election of group I and species of selective-serotonin reuptake inhibitors (SSRIs) as the drug class and interrupts pathways in the brain in the reply filed on November 17, 2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
The requirement is still deemed proper and is therefore made FINAL.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 265(c) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. PCT/EP2020/081273, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. Claim 1 permits the administration of a drug to any individual, cell line or cell model but the prior filed application only discloses administration to a mammal other than Homo sapiens or in vitro cell line or in vitro cell model a drug [sic] that can be from animals or patients that are presumably humans (top of p 6 of WO 2021/089772). The measuring step of claim 1 can take place before or after the drug administration step as there is no logic or grammar imposing order on the claimed steps (MPEP 2111.01(II)). These steps are not fully supported by the disclosure of the prior filed PCT application the discloses method measures the amount of glial fibrillary acidic protein (GFAP) in an individual previously exposed to the drug (¶ bridging p 5 and 6 of WO 2021/089772).
If Applicant is in disagreement with the Examiner regarding support for priority, Applicant is respectfully requested to point to page and line number wherein support may be found for the instant invention in the prior filed application.
This application repeats a substantial portion of prior Application No. PCT/EP2020/081273, filed November 6, 2020, and adds disclosure not presented in the prior application. Because this application names the inventor or at least one joint inventor named in the prior application, it may constitute a continuation-in-part of the prior application. Should applicant desire to claim the benefit of the filing date of the prior application, attention is directed to 35 U.S.C. 120, 37 CFR 1.78, and MPEP § 211 et seq. The presentation of a benefit claim may result in an additional fee under 37 CFR 1.17(w)(1) or (2) being required, if the earliest filing date for which benefit is claimed under 35 U.S.C. 120, 121, 365(c), or 386(c) and 1.78(d) in the application is more than six years before the actual filing date of the application.
As no claim under examination limits the claimed subject matter to that fully supported by the disclosure of the prior filed Application, the effective filing date of claims 1 – 9 is May 6, 2022.
Comments and Notes
It is noted that the claim amendments filed May 6, 2022, the filing date of the instant application, are not properly formatted. For example, clam 1 has a status identifier of “Original” but contains at least substantial deletions that are not indicated using strikethrough and should therefore have a status identifier of “Presently amended”. Failure to properly format future claim amendments may result in the mailing of a Notice of Non-Compliant Amendment.
Specification
The specification is objected to as failing to provide proper antecedent basis for the claimed subject matter. See 37 CFR 1.75(d)(1) and MPEP § 608.01(o). Correction of the following is required: as detailed above in the priority section, the full scope of the claimed subject matter is not supported by the disclosure of prior Application No. PCT/EP2020/081273, whose specification is identical to that of the instant application, and therefore the claimed subject matter lacks proper antecedent basis in the specification.
The specification is also objected to because the use of multiple trade names or marks used in commerce, has been noted in this application. Each term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM, or ® following the term.
Some but not all of the medications recited in ¶¶ [0029] and [0030] are trade names and not common names such as buspirone HCl.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 1 and 5 are objected to because of the following informalities: the abbreviations GFAP and GABA are not accompanied by the complete phrase the first time each of these abbreviations is used in the claims. Appropriate correction is required.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1 – 9 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more. The claim(s) recite(s) a method of assessing the cellular toxicity of a drug by performing a mental comparison of a measured value with a control measurement to indicate toxicity of a drug. This judicial exception is not integrated into a practical application because the steps that are not an abstract idea are required to collect the necessary data to carry out the judicial exception. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because additional steps are present that add significantly more than the judicial exception in either the independent or dependent claims.
The physical method steps required are administering of a drug to either an individual or an in vitro cell line or model and measuring GFAP in the cell line/model or an in vitro sample taken from the individual, which need not be after drug administration. Both of these steps are required to obtain the information for the comparison step of comparing the GFAP level to a control measurement, with the measured value being higher than the control indicating cellular toxicity. That such physical steps are required to carry out the abstract ideas does not result in the required integration into a practical application to result in significantly more than the judicial exception and render then claimed method drawn to patent eligible subject matter and there are no other steps that could result in significantly more.
Claim Rejections - 35 USC § 112 – Scope of Enablement
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 – 9 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 assessment of cellular for toxicity of a drug whose mechanism of action is not inhibition of GFAP in cells when assessing cells that express GFAP after administration of drug being studied for potential toxicity, does not reasonably provide enablement for the full scope of the claimed method. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The disclosure and claims of the application have been compared per the factors indicated in the decision In re Wands, 8 USPQ2nd 1400 (Fed. Cir. 1988) as to undue experimentation
The factors include:
1. The nature of the invention;
2. The breadth of the claims;
3. The predictability or unpredictability of the art;
4. The amount of direction or guidance presented;
5. The presence or absence of working examples
6. The quantity of experimentation necessary;
7. The state of the prior art; and
8. The relative skill of those skilled in the art.
Each relevant factor is addressed below on the basis of comparison of the disclosure, the claims and the state of the art in the assessment of undue experimentation.
The nature of the invention; the breadth of the claims:
The invention is a method with two physical steps and a comparison step. A drug is administered either to an individual or an in vitro cell line or cell model. The individual or cells used in this step are not limited. The amount of GFAP is measured in either “an in vitro sample taken from the individual” or the cells from the cell line/model. A comparison step with a control measurement is carried out, with a greater GFAP concentration in the cells “being indicative of cellular toxicity”. The claims do not clearly limit the assessment of toxicity to those cells whose GFAP levels might be altered and could be any cells in the subject including those that do not express GFAP (see below for additional discussion on this point). A definition of “control measurement” is set forth in the instant specification at ¶ [0018] which while indefinite as discussed in greater detail below is based on healthy individuals and not those with conditions such as depression.
The predictability or unpredictability of the art; the amount of direction or guidance presented; the presence or absence of working examples; the quantity of experimentation necessary; the state of the prior art; the relative skill of those skilled in the art:
The relative skill of those skilled in the art is relatively high, such as toxicologist or medical researcher investigating drug toxicity. GFAP, glial fibrillary acidic protein, is a known protein uniquely found in astrocytes of the central nervous system, non-myelinating Schwann cells in the peripheral nervous system and enteric glial cells (abstract of Yang et al., Trends Neurosci, 105). Therefore GFAP is not expressed in all cells of the body but only in select cells. The utility of GFAP as a neurotoxicity biomarker tool during drug development is known (p 372, col 1, ¶ 1 of Yang et al. and Cookson et al.; Toxic in vitro, 1994, whole document). Cookson et al. discloses that GFAp expression is upregulated after exposure to a chemically diverse set of toxic chemicals and is a consistent biomarker for astrogliosis, a set of hyperplasic and hypertrophic responses that occurs in response to physical damage, some disease states or exposure to toxic substances (p 351, col 1). Cho et al. (Human Mol Genetics, 2010 screened for compounds that suppress GFAP expression (e.g., title) and one compound that was investigated was the tricyclic antidepressant clomipramine (e.g., p 3171). As shown in Figure 1B and 1E, increasing clomipramine concentration showed greater reductions in GFAP promoter and protein level but toxicity was observed at 20 µM (figure 2 legend). Toxicity was measured using the CellTiter-Glo® assay (p 3170, col 1, ¶ 2) and occurred despite decreased GFAP levels. Rajkowska et al. indicates that GFAP expression varies in younger and older patients with MDD (major depressive disorder) with immunoreactive GFAP (GFAP-IR) decreasing in a mixture of younger and older MDD patients with increases seen in older subjects with late onset depression and in the hippocampus of patients with MDD not treated with antidepressants (p 3, ¶ 3). At least some treatments for depression including drugs such as certain serotonin-selective reuptake inhibitors (SSRIs), electroconvulsive therapy and transcranial magnetic stimulation can alter GFAP expression (p 4, ¶ 4 – p 5, ¶ 1).
The specification as filed contains a single study comparing participants with and without PTSD (post-traumatic stress disorder) and it appears either with or without depression and with or without medication (¶ [0027] onward of the PGPub of the instant application) and analyses of biomarkers including GFAP was carried out (¶ [0032]) in the various subjects. No studies related to cellular toxicity are reported.
The GFAP measurement step only provides relevant information about potential toxicity when carried out after the drug administration step but the measurement step can either take place before or after drug administration.
GFAP is a known marker of cellular toxicity but is only expressed in a few types of cells and increased levels of this protein can also be indicative of treatment of conditions such as depression and decreased levels of GFAP are associated with untreated depression and not necessarily cellular toxicity even with agents that are known to be toxic to such cells. There is no evidence that exposure to toxic chemicals results in GFAP expression in cells that do not normally express GFAP as the cited art used astrocytes that express GFAP and the neurotoxicity of the agents towards astrocytes was studied. Therefore the claimed method is not fully enabled for the assessment of cytotoxicity when cells that are now known to express GFAP are used in the in vitro cell line or cell model experiments. The therapeutic effects of the drug being screened can impart a confounding factor that can prevent determination of cellular toxicity based on GFAP amounts compared to a control measurement. Drugs that act to suppress GFAP expression as in Cho et al. could be interpreted as non-cytotoxic despite them being indicated as such by Cho et al. The control measurement appears to be based on healthy individuals, so assessment of an antidepressant in a subject with MDD as discussed in Rajkowska et al. could increase GFAP levels from the decreased levels noted in MDD and interpreted as having no toxicity when compared with GFAP levels from a healthy individual or even indicated as cytotoxic depending on the extent of the increase in GFAP seen with drug administration.
Therefore, when the relevant Wands factors are compared, the full scope of the instant claims is not enabled.
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 – 9 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.
One possibility for the measurement step in claim 1 is “an in vitro sample taken from the individual” (emphasis added). A sample can be collected from a subject and then analyzed and that would be an in vitro measurement. But what constitutes an in vitro sample that is taken from an individual is not clear and neither the claims nor the specification defines this phrase to indicate what constitutes such a sample.
¶ [0018] of the PGPub of the instant application attempts to define “control measurement” as recited in claim but the definition is not sufficient to adequately define the metes and bounds of the claims. The phrase is stated to be “understood to be the level of GFAP typically found in healthy individuals” and also indicates that such values “can be calculated by the user … by reference to typical values provided by the manufacturer of the assay used to determine the level of biomarker in the sample”. What is considered typical or values provided by an assay manufacture could change over time and/or people of ordinary skill in the art may not all agree on what constitutes a typical level found in a healthy individual. Therefore the complete metes and bounds of the claims cannot be determined.
The dependent claims fall therewith.
Please clarify.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1 and 2 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Cookson et al. (Toxic in Vitro, 1994).
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).
Claim(s) 1 – 4, 8 and 9 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Cho et al. (Human Mol Genetics, 2010).
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.
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 – 9 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).
Cookson et al. is discussed above.
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.
Claim(s) 1 – 9 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).
Cho et al. is discussed above.
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.
Conclusion
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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/Nissa M Westerberg/Primary Examiner, Art Unit 1618