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 .
Priority
This application filed, 20 January 2023 is a 371 of PCT/HU/2021/000011 filed on 21 July 2021 and claims priority to Hungary application No. P2000240 filed on 22 July 2020.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/17/2025 was filed after the mailing date of the Non-Final Action. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Withdrawn Rejections
The rejection of claims 1-2 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn in view of Applicant’s amendments to the claims.
The rejection of claims 1-2 under 35 USC 112(a) as lacking written description for a method of detecting Alzheimer’s disease comprising detecting SDC-3 using an antibody specific thereto is withdrawn in view of Applicant’s arguments. However, these claims are still rejected because adequate written description is not found for “ligand specific to SDC-3”.
Claim Rejections - 35 USC § 112
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 1-2 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 written description rejection.
This rejection has been modified based on Applicant’s arguments and supports for antibody specific to SDC-3. It is acknowledged that Applicant shows proper possession of a method for diagnosing Alzheimer’s disease by detecting SDC-3 expression by monocytes isolated from systemic circulation using antibodies specific to SDC-3, Applicant has not provide adequate written description and possession of “ligand specific to SDC-3”.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the Application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient.” MPEP § 2163. While all of the factors have been considered, a sufficient amount for a prima facie case are discussed below.
Further, to provide evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include: a) the scope of the invention; b) actual reduction to practice; c) disclosure of drawings or structural chemical formulas; d) relevant identifying characteristics including complete structure, partial structure, physical and/or chemical properties, and structure/function correlation; e) method of making the claimed compounds; f) level of skill and knowledge in the art; and g) predictability in the art. See MPEP 2163.
Claims 1 and 2 are directed to a method of diagnosing Alzheimer’s disease by measuring the syndecan-3 (SDC-3) expression of monocytes isolated from systemic circulation with an antibody or any other ligand specific to the 442 amino acid protein of SDC-3. The scope of the claims therefore cover any and all ligands specific to the 442 amino acid protein of SDC-3 where the ligand must possess certain functional characteristics, namely the ability to bind to the 442 amino acid protein of SDC-3.
While the specification discloses one APC-labeled human syndecan-3 antibody from R&D System and the use of a mouse syndecan-3 ELISA kit containing two human syndecan-3 antibodies (a capture antibody and a detection antibody), the specification does not identify any structure, partial or otherwise, common to the members of the genus of “ligand specific to SDC-3”. Although the claims refers to ligands with the desired function, the scope of the claims encompasses a virtually unlimited number of ligands comprising deletions, substitutions, insertions, and any other medications. As a result, there is not necessarily any partial structure that is common to the members of the genus.
While the level of skill in the art is high, insofar as methods for making and/or screening recombinant protein variants were well known in the art at the time of the invention. At the same time, however, it was not within the skill of the art to reliably predict whether a particular variant would possess desired binding properties.
In particular, there is no specific guidance provided as to which ligands can be used and how they can be made such that the desired functional characteristics can be achieved. It is noted that even small changes in antigen structure can profoundly affect antigen binding interactions.
For example, Harlow et al. (Harlow, E. and Lane, D., Antibodies: A Laboratory Manual (1988) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, pages 23-26), who teach that the loss of a single hydrogen bond can dramatically affect the ability of an antibody to recognize a cognate antigen (see especially page 26, first full paragraph).
Lederman et al. ("A single amino acid substitution in a common African allele of the CD4 molecule ablates binding of the monoclonal antibody, OKT4" Mol Immunol. 1991 Nov;28(11):1171-81) found that a single amino acid substitution on the antigen CD4 ablated binding of a monoclonal antibody (see title and abstract). Similarly, Colman et al. (Research in Immunology, 1994; 145(1): 33-36) teach that amino acid changes in an antigen can effectively abolish antibody antigen binding entirely (see entire document, particularly pages 33-34). Brown et al. (J Immunol. 1996 May;156(9):3285-91 at 3290 and Tables 1 and 2), describes how a one amino acid change in the VHCDR2 of a particular antibody was tolerated whereas, the antibody lost binding upon introduction of two amino changes in the same region.
Moreover, at the time of the invention, it was recognized that analysis of a given amino acid sequence only provides rough guides as to whether the sequence will bind to an antibody. See Lesniewski et al. (U.S. 6,596,476 B1) at column 5, lines 40-47, who further teach that there is no invariably predictable way to ensure whether a sequence has immunological activity short of preparing the sequence and testing it in an assay.
In view of the above, it cannot be predicted what ligands could be made to retain the ability to bind to syndecan-3.
The importance of structure/function correlations was recently highlighted by the courts (Abbvie Deutschland v. Janssen Biotech and Centocor Biologics, App. No. 2013-1338, 1346 (Fed. Cir., July 1, 2014)). The Abbvie case involved antibodies and written description. The court stated: “We have held that “a sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Id. at 1350 (quoting Eli Lilly, 119 F.3d at 1568– 69).”. The courts then further stated: “With the written description of a genus, however, merely drawing a fence around a perceived genus is not a description of the genus. One needs to show that one has truly invented the genus, i.e., that one has conceived and described sufficient representative species encompassing the breadth of the genus. Otherwise, one has only a research plan, leaving it to others to explore the unknown contours of the claimed genus.” (emphasis added) and then state: " Functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. Ariad, 598 F.3d at 1351 (“[T]he level of detail required to satisfy the written description requirement varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology.”); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1352 (Fed. Cir. 2011) (noting the technical challenges in developing fully human antibodies of a known human protein). It is true that functionally defined claims can meet the written description requirement if a reasonable structure-function correlation is established, whether by the inventor as described in the specification or known in the art at the time of the filing date. Enzo Biochem, Inc. v. Gen-Probe Inc., 323 F.3d 956, 964 (Fed. Cir. 2002). However, the record here does not indicate such an established correlation.
The specification does not provide any suggestions for how to make and use the claims as written. While one could test a plurality of antibodies and ligand to determine which, if any, have the required functional characteristics as claimed, a “mere wish or plan” for obtaining the claimed functional is not adequate written descriptions. . See Regents of the Univ. of Cal. v. Eli Lilly & Co., 119 F.3d 1559, 1566 (Fed. Cir. 1997); and Centocor Ortho Biotech Inc. v. Abbott Laboratories, 97 USPQ2d 1870 (Fed. Cir. 2011). This gives rise to a situation in which the actual inventive work of producing at least a substantial number of the claimed antibodies and ligands would be left for subsequent inventors to complete.
For these reasons, the specification does not adequately describe the claimed genus of ligands or the claimed methods of use.
Claim Rejections - 35 USC § 103
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 (i.e., changing from AIA to pre-AIA ) 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.
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.
Claims 1-2 are rejected under 35 U.S.C. 103 as being unpatentable over Letoha et al (Contribution of syndecans to cellular internalization and fibrillation of amyloid-β(1–42). Scientific Reports. 2019. 9:1393) in view of Wegrowski et al (Cell surface proteoglycan expression during maturation of human monocytes-derived dendritic cells and macrophages. Clinical and Experimental Immunology. 144: 485–493. 2006) and Lonneborg (Biomarkers for Alzheimer Disease in Cerebrospinal Fluid, Urine, and Blood. Mol Diag Ther 2008; 12 (5): 307-320. 2008)
Letoha discloses the role of syndecans, specifically syndecan-3 (SDC-3), in Alzheimer’s disease (AD), a neurodegenerative disease. Letoha teaches that colocalization of amyloid plaques with members of the syndecan family of HSPGs, along with the increased expression of syndecan-3 and -4 have been known in postmortem AD brains. The neuron specific syndecan-3 isoform increased cellular uptake of Aβ1–42 the most and SDC-3 increased Aβ1–42 uptake from the earliest time point. See Abstract. SDC3 has been shown to be significantly increased in human AD brain and through modulating Aβ aggregation and clearance they promote amyloid pathology. SDC-3 is found to be associated with the majority of senile plaques in AD brains. See last paragraph of page 1 bridging page 2. Letoha discloses data highlighting SDC3 isoform as important players in the amyloid pathology of AD and show that SDCs, regardless of cell type, facilitate key molecular events in neurodegeneration. Letoha teaches detecting SDC-3 by flow cytometry using APB-labeled anti-SDC-3 antibody. See page 11, Figure 8 and page 13, co-immunoprecipitation experiments. Letoha teaches that SDC3 overexpression, regardless of cell type, can contribute to fundamental biological processes (i.e. uptake and fibrillation) related to Aβ1–42 pathology, and highlights SDC3 with increased expression in AD brains as important players in the pathophysiologic events of neurodegeneration. See page 12, first paragraph.
Letoha differs from the instant claims in failing to teach the detection of SDC-3 expression of monocytes isolated from systemic circulation.
Wegrowski discloses peripheral blood monocytes expresses a characteristic set of cell surface receptors which is correlated with the expression of characteristic cell surface proteoglycans including SDC-3. See page 490, Discussion and page 491, Table 3. Wegrowski also teaches SDC-4 is expressed in a ubiquitous fashion while SDC-1 and SDC-3 are more restricted to epithelial cells and neurons, respectively.
Lonneborg teaches various biomarkers for AD and their potential to aid in a correct diagnosis. Novel biomarkers that use blood and urine, the more easily available clinical samples are also being discovered and developed. See Abstract. Lonneborg teaches an ideal biomarker should be reliable, reproducible, non-invasive, simple to perform and inexpensive. See page 308, right column. Lonneborg discloses AD is associated with profound biochemical and pathologic alterations in the brain, including aberrant amyloid precursor protein (APP), amyloid-β (Aβ) protein metabolism, tau protein phosphorylation, oxidative stress, inflammation, and lipid dysregulation. See page 308. Specifically, Lonneborg teaches biomarkers in blood for the detection of AD is greatly desired. Potential biomarkers that are closely associated with brain pathophysiology are restricted to small molecules, lipophilic molecules, and molecules with specific transporters. See page 311, right column, #3 Biomarkers in Blood.
Given the collective teachings above, it would have obvious to one of ordinary skill in the art before the effective filing date of the instant invention to modify the method taught by Letoha for diagnosing AD by detecting SDC-3 in blood samples such as taught by Wegrowski because Wegrowski teaches that SDC-3 is expressed in monocytes in systemic circulation (i.e. pheripheral blood monocytes) and Lonneborg teaches the desirability of a biomarkers that maybe detected in samples that are easily collected such as blood. Letoha teaches that SDC-3 is a neuron specific glycan and is closely associated with increased Aβ1–42 and its overexpression in AD samples makes it a highly desirable biomarkers for diagnosing AD and Wegrowski demonstrates that monocytes expressing SDC-3 may be detected in systemic circulation, therefore, a skilled artisan would have had a reasonable expectation of success in diagnosing AD by detecting SDC-3 expression of monocytes in peripheral blood sample using the commercially available anti-SDC-3 antibodies taught by Letoha because assays such as taught is well known in the art and Wegrowski teaches that monocytes expressing SDC-3 may be detected using RT-PCT or flow cytometry and Lonneborg teaches novel biomarkers for AD use blood is more easily available as a clinical sample and the SDC-3 taught by Letoha meets all of the limitation of a desirable biomarker for AD, mainly it is closely associated with brain pathophysiology are restricted to small molecules, lipophilic molecules, and molecules with specific transporters.
For the reasons above, claims 1-2 are rejected.
Response to Arguments
Applicant's arguments filed 05 December 2025 have been fully considered but they are not persuasive.
Applicant argues that the prior art combination of Letoha, Wegrowski and Lonneborg does not make obvious the claimed invention because Letoha does not teach measuring SDC-3 in pheripheral blood and does not disclose SDC-3 expression in monocytes in the context of Alzheimer’s disease. While Wegrowski teaches SDC-3 expression in monocytes in the context of Alzheimer’s disease, Applicant argues that Wegrowski teaches away from using SDC-3 as a biomarker for the same because the protein has minimal expression on monocytes. And finally, Lonneborg does not identify SDC-3 as a candidate biomarker.
These arguments are not persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
SDC-3 is a known biomarker of Alzheimer as recognized by Letoha and Wegrowski. While Letoha does not disclose that SDC-3 may be detected in pheripheral blood monocytes, Letoha teaches SDC-3 is positively linked to AD, and Wegrowski clearly teaches SDC-3 expression on blood monocytes and also discloses that this biomarkers is associated with AD. The fact SDC-3 is minimally expressed on monocytes does not teach away as argued by Applicant. There is no evidence that SDC-3 cannot be detected even if it is not expressed in abundance in blood monocytes. It is well known in the art and as taught by Lonneborg that non-invasive biomarkers that may be obtained quickly and painlessly from the body without invasive procedures is an advantage. Further, Lonneborg teaches various blood biomarkers that maybe used to diagnose AD. Therefore, given the combination of the prior art, a skilled artisan would have been motivated to detect SDC-3 in blood monocytes and using such result to diagnose AD. Applicant has not provided any evidence beyond arguments that such detection does not work.
For the above reasons, all claims are rejected and no claims are allowed.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
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/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677 March 6, 2026