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
1. Applicant's election with traverse of species of syndecan-4 and VE-cadherin in the reply filed on March 11, 2026. However, since Applicant did not present any arguments to traverse the restriction, response to restriction requirements is considered as election without traverse. MPEP 818.03(a). The requirement is still deemed proper and is therefore made FINAL.
2. Claim 5 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on March 11, 2026.
3. Claims 1, 6-24 and 30 are under examination.
Claim Objections
4. Claims 23 and 24 are objected to because of the following informalities:
The claims recite “AD” without first providing the full name of the term. It is suggested that the term be spelled out at its first use and in all independent claims so that it is clearly understood what it stands for. Appropriate correction is suggested.
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.
5. Claims 1, 6-18, 20-22, 24 and 30 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.
6. The term “elevated” in claims 1 and 7 is a relative term which renders the claims indefinite. The term “elevated” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Providing a point of reference or comparison within the claims would obviate this ground of rejection.
7. Further, claims 1 and 7 encompass detecting the levels of markers without specifically pointing out where, such as in a sample obtained from the subject under testing or generally measuring the total content within the body or anything else. This renders the claims indefinite.
8. Claim 1 is further indefinite for reciting limitation “treating the subject accordingly,” which in view of the absence of positive, physical and repeatable steps appears subjective. Amendment to recite specific objective steps to support the limitation would obviate this ground of rejection.
9. Claim 6 recites the limitation "additional biomarkers" in claim 1. There is insufficient antecedent basis for this limitation in the claim, see “endothelial markers” in claim 1.
10. Claim 8 does not make sense. Specifically, the claim encompasses a step of treating the subject “differently;” however, first, it is not clear how to compare the first subject who has elevated levels of markers as in claim 7 to the second in which “the markers were not detected,” and, second, it is not obvious what stands for a different treatment. Applicant is advised to rewrite the claim to better express claimed subject matter.
11. Claim 11 is indefinite for reciting limitation “biomarker evidence of AD pathology.” The metes and bounds of the limitation cannot be determined from the claim or the specification as filed.
12. Claim 12 recites the limitations "Alzheimer’s disease," “Parkinson’s disease” and “Frontotemporal dementia” in claim 7. There is insufficient antecedent basis for these limitations in the claim.
13. Claim 13 recites limitation “wherein the subject is also measured for tau” etc., which is grammatically awkward and therefore indefinite. Briefly, if the claim intends to encompass measuring the levels of additional biomarkers, then this what should be presented within the claim to avoid ambiguity of claim interpretation.
14. Claims 14 and 15 are indecipherable as written. Briefly, it is not clear and cannot be determined from the claims or the specification as filed what stands for endothelial markers prediction of clinical progression of AD over time, or for prediction of cognitive impairment in cognitively normal subjects. Applicant is advised to rewrite the claims to better express claimed subject matter using positive terms and active verbs so that there is no uncertainty as what is claimed.
15. The terms “increase” and “decrease” in claims 20 and 22 are relative terms which renders the claims indefinite. These terms are not defined by the claims, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Proving a point of reference or comparison within the claims would obviate this ground of rejection.
16. Claims 21 and 24 describe composition as “used to treat,” and it is not obvious whether it refers to general description of the composition or to an active step of using it. This renders the claims indefinite.
17. Claim 30 is vague and ambiguous as being directed to a kit comprising antibodies for detecting at least syndecan-4 and VE-cadherin, the elected species, and it is not obvious whether the kit comprises two types of antibodies —antibodies for detecting syndecan-4 and antibodies to detect VE-cadherin— or antibodies for detecting two of the markers together. Clarification is required.
18. Claims 9, 10 and 16-18 are indefinite for being dependent from indefinite claims.
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.
19. Claims 1 and 6-24 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 treating Alzheimer’s disease (AD) by detecting elevated levels of syndecan-4 and VE-cadherin in a sample of CSF obtained from the subject under testing and administering a treatment for AD, does not reasonably provide enablement for the full scope of invention as currently in claims. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
Claims 1 and 6 encompass methods of diagnosing and treating endothelia injury in a subject. Claims 7-18 are drawn to a method of diagnosing and treating neurodegenerative disorders, AD among them. Claims 19-24 are directed to methods of monitoring effects of a composition on endothelial injury in a subject. However, the specification does not provide sufficient guidance to enable practice the full scope of the claimed invention without undue experimentation.
The enablement requirement is met when one skilled in the art, having read the specification, could practice the invention without “undue experimentation.” Cephalon, Inc. v. Watson Pharm., Inc., 707 F.3d at 1336 (Fed. Cir. 2013). The factors to be considered in determining whether a disclosure would require undue experimentation 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. In re Wands, 8 USPQ2d, 1400 (CAFC 1988).
The specification discloses endothelial injury as “a common and important mechanism in the pathogenesis of many neurological disorders,” p. 1. The list of neurological disorders is presented with [0005], pp. 1-2. The experimental results of working examples, pp. 28-38, are limited to studies of differential expression of syndecan-4 and VE-cadherin in samples of CSF obtained from patients with Alzheimer’s disease, Examples 1, 2 and 5, Figures 1, 2 and 5A. The instant specification provides no information related to diagnosis of endothelial injury in general, to diagnosis of neurological disorders other than AD, and no meaningful guidance for the invention of claims 19-24—monitoring effects of a composition on endothelial injury to treat the subject under testing and treatment and adjust the dose of the composition—thus, requiring undue experimentation on part of one skilled in the art to discover how to practice the claimed invention.
The nature of the invention involving biological molecules and their effect on a physiological system is complex and unpredictable. As was found in Ex parte Hitzeman, 9 USPQ2d 1821 (BPAI 1987), a single embodiment may provide broad enablement in cases involving predictable factors such as mechanical or electrical elements, but more will be required in cases that involve unpredictable factors such as most chemical reactions and physiological activity. This 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). See also In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970); Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 927 F.2d 1200, 1212, 18 USPQ2d 1016, 1026 (Fed. Cir.), cert. denied, 502 U.S. 856 (1991).
The prior art recognizes syndecan-4 and VE-cadherin as endothelin cell markers, see Nikmanesh et al., Biotech and Bioengineering, 2019, 116:2730-41. The art further teaches decreased levels of VE-cadherin in blood samples obtained from patients with AD, see US 11,193,946 (see citation to PCT publication date establishing the priority). However, finding of syndecan-4 and VE-cadherin as being elevated any in samples obtained from a subject with endothelial injury or suffering from any neurological disorder has not been reported.
With respect to claim breadth, the standard under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, entails the determination of what the claims recite and what the claims mean as a whole. In addition, when analyzing the enablement scope of the claims, the teachings of the specification are to be taken into account because the claims are to be given their broadest reasonable interpretation that is consistent with the specification (see MPEP 2111 [R-1], which states that claims must be given their broadest reasonable interpretation. “During patent examination, the pending claims must be "given *>their< broadest reasonable interpretation consistent with the specification." In re Hyatt, 211 F.3d 1367, 1372, 54 USPQ2d 1664, 1667 (Fed. Cir. 2000). Applicant always has the opportunity to amend the claims during prosecution, and broad interpretation by the examiner reduces the possibility that the claim, once issued, will be interpreted more broadly than is justified. In re Prater, 415 F.2d 1393, 1404-05, 162 USPQ 541, 550- 51 (CCPA 1969).”
As such, the broadest reasonable interpretation of the claimed methods is that they allow the detection of any type of endothelial injury and any type of neurodegenerative disorder, as well as monitoring effects of any composition on treatment of any endothelial injury and is not particularly limited to specific type of injury or particular disorders. Thus, the claims encompass an unreasonable number of pathological conditions, which the skilled artisan would not know how to evaluate. As opposed to the claims, what is disclosed about the claimed method is narrow: a set of examples limited to samples of CSF only and to Alzheimer’s disease and no other obvious specific examples of types of endothelial injuries, neurodegenerative disorders, compositions suitable for administration and examples of changes in the levels of markers during the treatment, or any other meaningful guidance as how to practice the full scope of instant claimed methods.
Applicant has left those skilled in the art with too much experimentation to research and discover for themselves the association, if any, of the levels of syndecan-4 and VE-cadherin in any biological sample obtained from subjects under testing and pathologies of endothelial injury and neurodegenerative disorders. The art does not teach that elevated levels of syndecan-4 and VE-cadherin are directly associated with endothelial injury and neurodegenerative disorders in general. The specification does not teach how to make decisions about the critical levels, particular diseases or choice of sample. As such, Applicant has merely provided a starting point for research and experimentation and not a meaningful enabling disclosure of how to practice the claimed invention. Therefore, the claimed invention clearly lacks enablement, as disclosed.
A mere wish or plan of obtaining the claimed invention is not sufficient. The standard of an enabling disclosure is not the ability to make and test if the invention worked but one of the ability to make and use with a reasonable expectation of success.
A patent is granted for a completed invention, not the general suggestion of an idea and how that idea might be developed into the claimed invention. If mere plausibility were the test for enablement under section 112, applicants could obtain patent rights to “inventions” consisting of little more than respectable guesses as to the likelihood of their success. In the decision of Genentec, Inc, v. Novo Nordisk, 42 USPQ 2d 100, (CAFC 1997), the court held that:
“[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable” and that “[t]ossing out the mere germ of an idea does not constitute enabling disclosure.” The court further stated that “when there is no disclosure of any specific starting material or of any of the conditions under which a process is to be carried out, undue experimentation is required; there is a failure to meet the enablement requirements that cannot be rectified by asserting that all the disclosure related to the process is within the skill of the art,” “[i]t is the specification, not the knowledge of one skilled in the art, that must supply the novel aspects of an invention in order to constitute adequate enablement.”
The instant specification is not enabling because one cannot follow the guidance presented therein and practice the full scope of the claimed methods without first making a substantial inventive contribution to perfect the methods and complete the invention.
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.
20. Claims 19-24 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more. Method claim(s) directed to monitoring changes in the levels of naturally occurring factors and assessing efficacy of treatment set forth laws of nature by reciting relationship between changes in the levels of naturally occurring factors and the pathology itself. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception for reasons that follow.
The subject matter eligibility under 35 U.S.C. 101 of natural products (i.e., whether the claimed product is a non-naturally occurring product of human ingenuity that is markedly different from naturally occurring products) was confirmed by the U.S. Supreme Court decisions including Association for Molecular Pathology v. Myriad Genetics, Inc., 569 U.S. , 133 S. Ct. 2107, 2116, 106 USPQ2d 1972 (2013), and Mayo Collaborative Services v. Prometheus Laboratories, Inc., 566 U.S. , 132 S. Ct. 1289, 101 USPQ2d 1961 (2012). "[L]aws of nature, natural phenomena, and abstract ideas" are not patentable. Diamond v. Diehr, 450 U. S. 175, 185 (1981); see also Bilski v. Kappos, 561 U. S. (2010). "Phenomena 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." Gottschalkv. Benson, 409 U. S. 63, 67 (1972).
In brief, in Prometheus, a method of optimizing therapeutic efficacy for treatment of an immune-mediated gastrointestinal disorder is the focus. This method comprises a) administering 6-thioguanine to patients and b) determining the level of 6-thioguanine in the patients and c) correlate the level of 6-thioguanine, i.e. a certain level/red blood cells, with the decision whether a need for increase or decrease the amount of 6-thioguanine treatment in said patients.
In Prometheus, the Court found that "[i]f a law of nature is not patentable, neither is a process reciting a law of nature, unless that process has additional features that provide practical assurance that the process is more than a drafting effort designed to monopolize the law of nature itself." Additionally, "conventional or obvious" "[pre]solution activity" is normally not sufficient to transform an unpatentable law of nature into a patent-eligible application of such a law." Flook, 437 U. S., at 590; see also Bilski, 561 U. S., ("[T]he prohibition against patenting abstract ideas 'cannot be circumvented by'.., adding 'insignificant post-solution activity'" (quoting Diehr, supra, at 191-192)).
The Court also summarized their holding by stating "[t]o put the matter more succinctly, the claims inform a relevant audience about certain laws of nature; any additional steps consist of well understood, routine, conventional activity already engaged in by the scientific community; and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately."
Thus, if the claim recites or involves a judicial exception, such as a law of nature/natural principle or natural phenomenon (e.g., the law of gravity, F=ma, sunlight, barometric pressure, etc.), and/or something that appears to be a natural product (e.g., a citrus fruit, uranium metal, nucleic acid, protein, etc.), then the claim only qualifies as eligible subject matter if the claim as a whole recites something significantly different than the judicial exception itself.
In the instant case, based upon an analysis with respect to the claim as a whole, claims 19-24 are determined to be directed to a judicial exception without significantly more. The rationale for this determination is explained below in view of controlling legal precedent set forth in 2014 Interim Guidance on Patent Subject Matter Eligibility (79 FR 74618) dated December 16, 2014 and 2019 Revised Patent Subject Matter Eligibility Guidance (84 FR 50) dated January 07, 2019.
The instant claims 19-24 are directed to a process. (Step 1: Yes).
Next, Step 2, is the two-part analysis from Alice Corp. (also called the Mayo test) to determine whether the claim is directed to laws of nature, natural phenomena, and abstract ideas (the judicially recognized exceptions). (In Alice Corp. v. CLS Bank Int’l, 134 S. Ct. 2347, 2354 (2014) the Supreme Court sets forth a two-step test for determining patent eligibility. First, determine if the claims encompass a judicial exception (a natural phenomenon/law of nature/abstract idea). If so, then ask whether the remaining elements/steps, 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.” Id. at 2355 (quoting Mayo, 132 S. Ct. at 1297). Put another way, there must be a further “inventive concept” to take the claim into the realm of patent eligibility. Id. at 2355. In the recent Myriad v Ambry case, the CAFC found claims (drawn to methods comprising obtaining tissue samples, analyzing sequences of cDNA and comparing germline sequences of a gene to wild-type sequences) to encompass the abstract mental processes of ‘comparing’ and ‘analyzing’. Recitation of specific techniques (in Myriad claims 7 and 8 further recited hybridization and PCR) were deemed not “enough” to make the claims patent-eligible since the claims contained no otherwise new process. The elements/steps recited in addition to the judicial exception did nothing more than spell out what practitioners already knew). The instant claims 19-24 encompass changes in the levels of syndecan-4 and VE-cadherin during pathology of endothelial injury and treatment thereof, the process that is governed by a law of nature, and thus is a judicial exception. The syndecan-4 and VE-cadherin are naturally occurring factors that are expressed differently during pathology of endothelial injury apart from any human action. The relation between the levels of expression of the syndecan-4 and VE-cadherin and pathology of endothelial injury exists in principle and is a consequence of the ways these factors are metabolized by the body, entirely natural process, a natural phenomenon, and thus a judicial exception (Step 2A/1: Yes). Next, prong two of Step 2A requires identifying whether there are additional elements recited in the claim beyond the judicial exception(s) and evaluating those additional elements to determine whether they integrate the exception into a practical application of the exception. “Integration in to a practical application” requires an additional element or combination of additional elements in the claim to apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception, such as the claim is more than a drafting effort designed to monopolize the exception. In the instant case, the claims do not recite any additional elements to integrate the judicial exception into a practical application because all the steps of the claimed methods are limited to only those that measure naturally occurring factors during a naturally occurring pathology. With respect to reciting steps of monitoring effects of treatment, the instant situation is similar to the one in Mayo, wherein the claims recited method of administering drugs to a patient and measuring the levels of certain metabolites in the blood, wherein the level of metabolites indicates whether to adjust the dosage. The Supreme Court held that the claims recited a natural law and did not “include any “additional features that provide practical assurance that the process is more than a drafting effort designed to monopolize the law of nature itself.” Mayo Collaborative Services v. Prometheus Laboratories, Inc., 566 U.S., 132 S. Ct. 77, 101 USPQ2d 1961 (2012). (Step 2A/2: No).
Finally, claims 19-24 do not recite any elements, or combinations of elements to ensure that the claim as a whole amounts to significantly more than the judicial exception because the active steps of the claims—detecting the levels of markers—represent routine steps that are recited at a high level of generality and encompass well-understood and purely conventional routine techniques in the art (see the specification at [00128], for example) (Step 2B: No).
Thus, for reasons fully explained above, claims 19-24 do not satisfy the requirement of 35 U.S.C. 101 and are therefore rejected.
Conclusion
21. No claim is allowed.
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/OLGA N CHERNYSHEV/Primary Examiner, Art Unit 1675
April 22, 2026
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