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 .
Detailed Action
Summary
This is the Final Office Action based on application 18/54460 RCE election response filed 10/03/2025 and in response to the remarks to the non-final action, remarks dated 07/09/2025.
Claims 27-28, 30-32, 38-39 & 41 are pending.
Claims 28 & 41 have been elected after restriction requirement since the scope of the originally pending claims was diverging to be different inventions. Claims 28 & 41 have been fully examined.
Claims 1-26, 29, 33-37, 40, & 42 have been cancelled.
Election/Restrictions
Applicant's election with traverse of Claims 28 & 41 in the reply filed on 10/03/2025 is acknowledged. The traversal is on the ground(s) that applicant thinks the groups of Claims require the same technical feature. This is not found persuasive because the groups do not share the same or corresponding technical feature.
The claimed detection/diagnosis in each of the groups is done in a technically different fashion using a different detection mechanism including detection of specifically different biomarkers/biomarker complexes. Though applicant argues against this, applicant admits in response dated 10/03/2023 that Claim 27 and 28 require CEL binding in very different technically different fashions as Claim 27 requires CEL-collagen XVII binding to a plate coated with collagen XVII antibodies, while claim 28 requires that the plate be coated with anti-CEL and anti-MGH1. These are technically different inventions and therefore the inventions have different technical features. Further, applicant makes no comment on Group III.
The requirement is still deemed proper and is therefore made FINAL.
Claims 27, 31-32, & 38-39 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 10/03/2025.
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 28 & 41 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.
With respect to Claim 28, “the accumulation ratio,” fails to have proper antecedent basis since “accumulation ration,” was not used before 7 lines from the bottom of Claim 28, where “the accumulation ratio,” is used. As this is the case, it is not clear if “the accumulation ratio,” is formed or calculated from other values already measured the in claim such as the “amount of CEL and MG-H1,” that was already claimed, or if accumulation ratio is something different such as what is standardly known in the art as how much things accumulate over time, or if applicant just means the ratio of CEL to MG-H1. Correction is required.
Claim 41 is rejected by virtue of being dependent on Claim 28.
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 ofmatter, or any new and useful improvement thereof, may obtain a patent therefor, subject to theconditions and requirements of this title.
The claimed invention of Claims 28 & 41 are directed to non-statutory subject matter.
The invention of instant claims 28 & 41 are drawn towards a method of diagnosis of neurodegenerative disease.
Through 101, inquiry analysis:
Step 1: Are the claims directed to a statutory category of invention?
Yes, the independent claim 28 is drawn towards a statutory category method.
Step 2A, Prong One: Does the claim involve a Judicial Exception?
Yes. Claim 28 involves a judicial exception of a law of nature which is a natural correlation which is the amount of CEL or MG-H1 and the accumulation ratio thereof with the correlation or diagnosis (presence) of a neurodegenerative disease.
Claim 28 also includes an “comparing,” step which is comparison of one value to another value and this is a mental process or at best when calculating the accumulation ratio to compare, a mathematical process, which is another judicial exception, which is an abstract idea.
Step 2A, Prong Two: Do the claims practically apply the judicial exception?
There are no features instantly claimed which practically apply the claimed natural correlation or abstract idea.
In addition to the natural correlation, in independent Claim 28 includes, “extracting,” “preparing,” “contacting,” “binding,” “detecting binding,” and “measuring,” and “comparing,” steps.
Though applicant has added more detail to the claims, none of what is claimed practically applies the judicial exceptions. Nothing is done after the diagnosis to practically apply. In fact, in the claims, nothing is done after the diagnosis occurs.
Further, the claimed, “extracting,” “preparing,” “contacting” (to a plate which has anti-CEL and ant-iMG-H1, antibodies bound thereto), “binding” (to the antibodies to induce an enzymatic reaction and color change), and “detecting binding,” and “measuring,” optical density values are steps are all performed as mere data gathering through with to accomplish the judicial exception and therefore are considered insignificant extra-solution activity. See MPEP 2106.05(g).
The fact that a ratio of two compounds to one another, which as claimed is the “accumulation ratio,” is measured does not change this fact. An accumulation ratio as understood is measuring of the ratio of the concentration of a compound at a steady state to the concentration after a single dose--- however as claimed, there is no dosing occurring, so this is read as measuring the concentration of the compound. Even if dosing was claimed—this still amounts to only making a measurement of a compound--- and it is still correlated with the claimed diagnosis.
Step 2B: Do the claims add significantly more to the judicial exception?
There are no features instantly claimed which result in significantly more than the claimed natural correlation or abstract idea.
In addition to the natural correlation, in independent Claim 28 includes, “extracting,” “preparing,” “contacting,” “binding,” “detecting binding,” and “measuring,” and “comparing,” steps.
Though applicant has added more detail to the claims, none of what is claimed adds significantly more to the judicial exceptions claimed.
The claimed, “extracting,” “preparing,” “contacting” (to a plate which has anti-CEL and anti-MG-H1, antibodies bound thereto), “binding” (to the antibodies to induce an enzymatic reaction and color change), and “detecting binding,” and “measuring,” optical density values are steps as claimed are all things that are well understood, routine and conventional (WURC) for laboratory practices in the art.
The claimed binding and measuring of the claimed antibodies reads similar to USPTO eligibility example 29 (Julitis claims), Claim 2, which was found ineligible. Further, when claimed that there is binding and enzymatic change to the plate, this is not claimed at a level that distinguishes it from well understood, routine, and conventional data gathering activity engaged in by scientists prior to applicant’s invention, and at the time the application was filed, e.g., the routine and conventional techniques of detecting using an antibody to that protein.
Further, it is well established that the mere physical or tangible nature of additional elements such as the obtaining and detecting steps does not automatically confer eligibility on a claim directed to an abstract idea (see, e.g., Alice Corp. v. CLS Bank Int’l, 134 S.Ct. 2347, 2358-59 (2014)).
Further, the fact that a ratio of two compounds to one another, which as claimed is the “accumulation ratio,” is measured does not change this fact. An accumulation ratio as understood is measuring of the ratio of the concentration of a compound at a steady state to the concentration after a single dose--- however as claimed, there is no dosing occurring, so this is read as measuring the concentration of the compound. Even if dosing was claimed—this still amounts to only making a measurement of a compound--- and it is still correlated with the claimed diagnosis.
See MPEP 2106.04 & 2106.05, 2106.05(d) which deals with what is considered “Well-Understood, Routine and Conventional”.
See USPTO eligibility examples, particularly example 29, Claim 2.
Nothing in the dependent claims change the matters above.
Claim 41 specifies that the comparison to a healthy control includes comparison to a curve (ROC) and indicates cutoff values for the diagnosis. Comparison to a curve/simple comparison to a cut-off value is a mental process/abstract idea judicial exception itself. The cutoff values are part of the natural correlation judicial exception itself. Therefore, this does not change the matters above.
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 28 is rejected under 35 U.S.C.103 as being obvious over HANSSEN in Measurement of advanced glycation endproducts in human plasma by ultra- performance liquid chromatography tandem mass spectrometry in view of TRELLU in Impairment of glyoxalase-1, an advanced glycation end-product detoxifying enzyme, induced by inflammation in age-related osteoarthritis and further in view of GRUBER in US 20200150131.
With respect to Claim 28, HANSSEN teaches of a method of measuring advanced glycation products/AGEs (title) in which the AGEs are known to be related to neurodegenerative diseases/disorders. HANSSEN further teaches that they determine the amount of carboxyethyl lysine (CEL), and the amount of MG-H1. HANSSEN further teaches that that levels measured are compared to healthy controls (Page 45, first two paragraphs). HANSSEN also teaches that though UPLC MS is preferred for determining the amounts of these compounds, that ELISA (which uses enzymatic reactions with anti- the compound detected antibodies) has also been used for the determination of their amounts (Page 54, paragraph 1). HANSSEN also teaches of determination of the accumulation of these AGE compounds (which include MG-H1 and CEL) (Page 10, paragraph 1, line 8) and of detecting the accumulation of them through fluorescence and autofluorescence (Page 14, paragraph 1).
HANSSEN does not teach specifically of determining the accumulation ratio of M-H1 specifically to CEL nor of measurement of optical density.
TRELLU is used to remedy this and more specifically teach of measuring accumulation of AGES (abstract). TRELLU further teach of measuring CEL and MG-H1 (Page 2, column 1, first paragraph) and of measuring accumulation(abstract). TRELLU further teach that all measurements of AGEs are expressed in a ratio with lysine (CEL) products (Page 3, column 2, paragraph 2, last two lines) (which reads on claimed accumulation ratio).
TRELLU also teaches of making spectrophotometric measurements (Page 4, column 2, lines 1-3). Spectrophotometry measures optical density and color change.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention and one would have had reasonable expectation of success to measure the accumulation ratio as is done in TRELLU in the method of HANSSEN due to the need in the art for better studies/analysis on AGE accumulation (TRELLU, page 1, column 2, last paragraph, Page 2, column 1, first paragraph) and it would have been obvious to one of ordinary skill in the art to measure before the effective filing date the optical density using spectrophotometry as is done in TRELLU in the method of HANSSEN due to the advantage this offers for measuring concentrations of compounds (TRELLU, Page 3, column 2, last paragraph).
HANSSEN and TRELLU do not teach of binding anti- MG-H1 and CEL antibody to a plate for detection.
GRUBER is used to remedy this and teaches of a method of making diagnoses using advanced glycation end products and antibodies thereof (abstract). GRUBER teaches that these compounds are used to diagnose Alzheimer’s and Parkinson’s diseases (paragraph 0032-0035). GRUBER more specifically teaches of the advanced glycation end (AGE) products being neurodegenerative related (paragraph 0002), and of the compounds which are AGE including carboxyethylysine (CEL) (paragraph 0004, 0022) and that the AGEs form from reaction with methyl glyoxal (paragraph 0004, 0114).
Specifically, GRUBER teaches that tissue samples are obtained from patients with various neurodegenerative diseases (paragraph 0113, 0112), or using cell extraction reagents and microtiter plates (paragraph 0065), which are ELISA plates with antibodies specific to the compounds detected thereon (paragraph 0069-0076).
While GRUBER focuses their examples on CML (carboxymethyllysine), GRUBER teaches that carboxyethyllysine can be used instead (paragraph 0022) and that antibodies against carboxyethylysine can be used on the plates which would be anti-CEL antibodies. GRUBER also teaches that any anti-AGE (advanced glycation product) antibody that binds to and AGE product/protein can be used (paragraph 0050- 0051). This makes using anti-MG-H1 antibody obvious as well since both TRELLU and SCHEIJEN teach of it as an AGE product.
GRUBER further teaches of detecting increased level of the AGEs (which would include carboxyethyllysine and MGH1 (though this one is not taught in GRUBER)) are part of and that the increased level are recognized as markers of disease (GRUBER, paragraph 0010), and of measuring accumulation of the AGEs and ratios thereof (GRUBER, paragraph 0003, 0043-0044). GRUBER also teaches of measuring ratios AGE’s to other AGEs (paragraph 0014, 0038, 0040-0041, 0044).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention and there would have been reasonable expectation of success to bind anti-AGE antibodies of AGE compounds to a plate to detect the levels of the compounds in a sample and diagnose neurodegenerative disease therefrom as is done in GRUBER in the methods of TRELLU And HANSSEN due to the fact that AGE levels are an accepted marker of diseases so there is expected success (GRUBER, paragraph 0010) and due to the advantages anti-AGE based diagnostics offer as being a minimally invasive and simple test which can be carried out in a doctors office (GRUBER, paragraph 0038).
Claim 41 is rejected under 35 U.S.C.103 as being obvious over HANSSEN in Measurement of advanced glycation end-products in human plasma by ultra- performance liquid chromatography tandem mass spectrometry in view of TRELLU in Impairment of glyoxalase-1, an advanced glycation end-product detoxifying enzyme, induced by inflammation in age-related osteoarthritis and further in view of GRUBER in US 20200150131 and further in view of LOPES in US 20110124119.
With respect to Claim 41, HANSSEN, TRELLU, and GRUBER teaches of the claimed invention as shown above for Claim 28. They do not teach of performing ROC analysis.
LOPES is used to remedy this. LOPES more specifically teaches of methods of measuring advanced glycation related products (abstract, paragraph 0008), of detecting Alzheimer’s disease (paragraph 0055), of detecting carboxyethyllysine (paragraph 0076), and performing ROC analysis (paragraph 0151, Table 3) using threshold values for comparison. The claimed cut-off values would follow naturally if a neurodegenerative disease is present, as this is how diagnostic science works. It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to perform ROC analysis and comparisons as is done in LOPES in the methods of HANSSEN, TRELLU, and GRUBER due to the advantage it offers for to comparison of the discriminatory power of various multivariate models (LOPES, paragraph 0151).
Response to Arguments
Applicant’s arguments with respect to claim(s) have been considered but are moot because the new ground of rejection does not rely on the combination of references applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
The claims have been significantly amended dated 07/09/2025, necessitating, new analysis of the claims and adjustment of the instant rejections. Therefore- the amendments and applicant’s arguments with respect to them are addressed by the rejections shown above.
The examiner notes that she has not responded to applicant’s arguments with respect to Claims 27, 31-32, & 38-39 and withdrawn due to election dated 10/03/2025 as they are drawn towards the non-elected inventions.
With respect to the 101 and prior art rejections, It is noted that the claims have been significantly amended and much detail was added to the claims. Therefore, these claims are addressed by the rejections shown above. Unfortunately, none of the added subject matter at the level of generality claimed reads on more than what is well understood, routine and conventional (these are things such as measuring optical density and binding anti-antibodies to plate surfaces and making detections therefrom, again especially at the level of generality these detections and the processing of the samples are claimed). Also- there is nothing claimed after the judicial exception is found, so not practical application. It is suggested that applicant review the USPTO subject matter eligibility example 29 to see what made some claims in that example allowable over others. The examiner notes that the prior art used in the instant rejection is the best which is found.
The 101 rejection is maintained, and further explained for the significantly amended claims as shown in the above rejection.
The prior art rejection, uses a new grounds of rejection and a new primary reference which was not used in the prior rejection, due to the amendments.
Applicant argues with respect to the Trellu reference that it teaches of the AGE compounds being related to osteoarthritis and not neurodegenerative disease as instantly claimed. With respect to this, the examiner notes that other references, including the primary reference teaches of relation of the AGE compounds to neurodegenerative disease.
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).
All claims remain rejected.
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 REBECCA M FRITCHMAN whose telephone number is (303)297-4344. The examiner can normally be reached 9:30-4:30 MT Monday-Friday.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maris Kessel can be reached on 571-270-7698. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/REBECCA M FRITCHMAN/Primary Examiner, Art Unit 1758