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 .
Status of Claims
Claims 1-5 are pending and will be examined on the merits.
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. 17/965,941, filed on 10/14/2022. The effective filing date of the invention is 10/15/2021.
Information Disclosure Statement
The Information Disclosure Statement filed on 10/28/2024 has been considered. Signed copies are enclosed.
Specification
The use of the term such as Sigma Aldrich on page 26, line 3, which is a trade name or a mark used in commerce, has been noted in this application. The 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.
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.
Applicant is required to carefully review the specification for trade names.
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.
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 1-5 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.
Where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999). The term “activity” in claim 1 is used by the claim to mean “expression" or "level,” while the accepted meaning is “enzymatic activity.” The term is indefinite because the specification does not clearly redefine the term. Claims 2-5 inherit this rejection as they do not correct it. Examiner notes that activity cannot be determined by simple protein quantification methods, such as those disclosed in the specification and in claim 5 (Western blot, ELISA, etc…).
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 1-5 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized in In re Wands (858 Fed 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)). The factors most relevant to this rejection are the scope of the claim, the nature of the invention, the state of the prior art, the level of ordinary skill in the art, the unpredictability in the art, the amount of direction or guidance provided, limited working examples, and the amount of experimentation required to enable one of skill in the art to make and use the claimed invention.
The instant claims are drawn to a specific purpose and scope – a method of diagnosing Alzheimer’s disease. Alzheimer’s disease is a specific disease with a known set of symptoms and characteristics.
The nature of the instant invention is drawn to a biomarker-based method of diagnosis, including measuring the level of PLCβ1 protein in a biological sample isolated from a subject. While one of ordinary skill in the art would understand how to measure the level or the activity of a protein in a sample, the correlation between the instant biomarker protein (PLCβ1) and the disease state (Alzheimer’s disease) is not necessarily supported by the art.
The pathology of Alzheimer’s disease is generally understood, as reviewed in Maccioni et al. (Archives of medical research vol. 32,5 (2001): 367-81), being characterized by the formation of senile plaques and neurofibrillary tangles (NFTs), which are involved in the process leading to progressive neuronal degeneration and death. Senile plaques are generated by a deposition in the human brain of fibrils of the β-amyloid peptide (Aβ), and NFTs are formed from anomalous tau phosphorylation, attributed to proteins such as Cdk5 and GSK3β (Maccioni et al., abstract). The association of PLCβ1 and Alzheimer’s disease has been noted in the art prior to the effective filing date. For example, Albasanz et al. (Neurobiology of Disease 20 (2005) 685 – 693) teach that basal PLCβ1 activity is decreased in later stages of Alzheimer’s disease, as well as in other neurodegenerative diseases, such as Lewy Body Dementia (see abstract and page 690, right column). More recently, Garwain et al. (Cellular Signalling 71, (2020), 109620) notes the downregulation of PLCβ1 significantly increases tau protein expression and causes a large increase in tau aggregation (see abstract, whole document). Despite this known association, PLCβ1 has not been relied upon as a biomarker for Alzheimer’s diagnosis.
In fact, the general role of biomarkers in Alzheimer’s diagnosis in the art is an accessory role at best. As reviewed in Monfared et al. (Neurol Ther (2023) 12:1257–1284), the recommended medical guidelines for diagnosing Alzheimer’s disease rely mainly on clinical symptoms to diagnose Alzheimer’s disease (see heading “Testing and Diagnosis” on pages 1276-77, Table 3, and Discussion section, page 1278). Summarized in Table 3 on page 1270, it is clear that biomarkers are not typically used for routine diagnosis, and are indeed advised against, as there are no biomarkers that have been conclusively demonstrated to predict disease progression. Additionally, when biomarkers are suggested, it is for investigating the underlying causes of the disease, not in typical diagnosis. Dubois et al. (Alzheimer’s Research & Therapy (2023) 15:175) reemphasizes this finding, stating that there is no biomarker that can differentiate between types of Alzheimer’s disease or conclusive accuracy, which underscores the importance of clinical presentation in diagnosis (page 5, left column). Dubois et al. outlines the current biomarkers considered to be hallmarks of Alzheimer’s disease in Figure 2, and does not include PLCβ1. Dubois et al. also emphasize that biomarkers should be complementary to clinical assessment, and most biomarkers agreed upon by experts in the field are only intended to be used in research settings (See subheading “Biomarkers should be complementary to clinical assessment for AD diagnosis” on pages 8-9). Finally, Dubois et al. disclose that, while biomarkers may be important for early detection of the disease, the diagnosis is restricted to patients with clinical presentations, and that biomarker-positive cognitively unimpaired individuals should be simply considered at-risk for progression to Alzheimer’s disease and dementia. Therefore, even if PLCβ1 could be considered a biomarker, detection of PLCβ1 would not necessarily support being a sole diagnostic factor, as in instant claim 1.
Finally, Khoury et al. teach the ideal biomarker for a disease should be specific, sensitive, simple, and easy to measure, in samples such as serum or urine, with a sensitivity and specificity of >80% considered optimal for a molecule to be a biomarker of Alzheimer’s disease (see introduction). Khoury et al. also discuss that biomarkers are present in significantly more individuals than those who present with clinical Alzheimer’s disease (conclusion, page 4, right column). Khoury et al., similar to Dubois et al. and Monfared et al., recite that the standard for diagnosis should remain clinical presentation and neuropsychological testing, and biomarkers are recommended for use in research settings to confirm and expand upon their reliability and validity, alone or in combination. Therefore, one of ordinary skill in the art of diagnosing Alzheimer’s disease would be a physician, who would know to focus more on clinical presentation, and would not know how to translate a biomarker result, such as that of the instant claims, into a diagnosis of Alzheimer’s disease. Additionally, while biomarkers can be linked to Alzheimer’s diseases cases, it is clear from Dubois et al. and Khoury et al. that it is unpredictable if a patient will develop clinical symptoms of Alzheimer’s disease, even when testing positive for biomarkers, indicating that the level of predictability in the art of Alzheimer’s disease progression and diagnosis is low.
With regards to the Applicant’s specification, the amount of direction provided on how to execute the claimed method is low. Applicant recites in the specification that “diagnosis” includes “determining the susceptibility of an object to a specific disease or disorder, determining whether an object currently has a specific disease or disorder, and determining the prognosis of an object with a specific disease or disorder” (page 22). Applicant recites, on page 23, that the sample of claim 1 may be any sample collected from a subject with Alzheimer’s disease; however, Applicant only shows increases in PLCβ1 protein level in brain tissue in the examples.
Regarding working examples, Applicant only provides one set of results on PLCβ1 protein expression, measured via Western blot in Example 4, on pages 38 and 39. The PLCβ1 levels are measured in homogenized mouse hippocampal slices from deceased subjects, not protein activity in living tissue or fresh samples. The working example does show a significant decrease in PLCβ1 levels in the Alzheimer’s disease model mice as compared to WT and treated.
Taken together, one would need to exercise an unreasonable amount of experimentation to effectively use the diagnostic method claimed, as one would need to detect PLCβ1 levels in living tissues, preferably from an easy to access sample such as blood or CSF. While this could be done by one skilled in the art, as discussed above, there is no predictability in if a person who is positive for this biomarker (decreased levels of PLCβ1) will develop clinical symptoms of Alzheimer’s disease or not. It is not routine to make an Alzheimer’s diagnosis based solely on the levels of a biomarker in a sample. Therefore, it would take one of ordinary skill in the art undue experimentation to determine how to translate a positive biomarker result with an Alzheimer’s diagnosis.
In view of the Wands factors as discussed above, one of ordinary skill in the art would have to engage in undue experimentation to practice the full scope of the instant claimed invention. As such, instant claims 1-5 are determined to not meet the enablement requirement of 35 USC § 112(a).
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Amelia Stephens whose telephone number is (571)272-1006. The examiner can normally be reached M-F 8-5 EST.
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/AMELIA STEPHENS/Examiner, Art Unit 1645
/ANNE M. GUSSOW/Supervisory Patent Examiner, Art Unit 1683
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