FINAL ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This action is responsive to the Amendment and Response filed 29 July 2026. Claims 1, 18, and 19 have been amended and claim 23 has been canceled. All prior rejections of claim 23 are moot in view of the cancelation of the claim. Claims 2-8 and 16 remain withdrawn, and claims 1, 10-11, 14-15, and 17-22 remain under consideration herein. Applicant’s amendments and arguments have been thoroughly reviewed, and Applicant’s amendments have overcome the prior rejections of claims under 35 USC 112(b) (although the claims remain indefinite for the reasons given below).
Claims 1, 10-11, 14-15, and 17-22 remain rejected for the reasons set forth below, which include new grounds of rejection necessitated by Applicant’s amendment. Any rejections and/or objections not reiterated in this action have been withdrawn. This action is FINAL.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Election/Restriction
Applicant’s election without traverse of the species of DAG1 in the reply filed on March 7, 2024 is again acknowledged.
Claims 2-8 and 16 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on March 7, 2024.
Claim Rejections - 35 USC § 112(b)/second paragraph
THE FOLLOWING INCLUDES NEW GROUNDS OF REJECTION NECESSITATED BY APPLICANT’S AMENDMENTS:
Claims 1, 10-11, 14-15, and 17-22 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.
Claims 1, 10-11, 14-15, 17, and 20 are indefinite because it is unclear from the language of amended independent claim 1 whether the claims do or not require an outcome in which “the concentration of DAG-1 in the isolated patient exosomes” are “greater than the control concentration of DAG-1” (see d) of claim 1), such that the boundaries of the claims are not made sufficiently clear by the present claim language. Some persons of skill in the art might interpret the claims as requiring that the “comparing” of c) have a positive outcome, and that the language “identifying the patient….based on the concentration….being greater” refers to a required outcome of the claims. However, the claims may also reasonably be interpreted as not requiring such an outcome (with the claims requiring a “comparing” that need or not result in the criteria of the “identifying” being met); factors in support of this interpretation include the lack of an actual recitation of a required outcome meeting the criterion referenced in the “identifying” of claim 1, the vague language “identifying the patient….based on the concentration…”, and the recitation of dependent claims that refer to a subject as “possibly suffering from said neurological disease/disorder” and include “wherein” language such as “wherein the concentration…is elevated” (in reference to other markers, whereas such language is lacking in the instant claims; see, e.g., withdrawn dependent claim 16, which Applicant has requested be rejoined as it is “requires all the limitations of claim 1” [see Reply at page 13]). Accordingly, as there are multiple reasonable interpretations of the claim language that impart different boundaries on what is being claimed, further clarification is required.
Claims 18 and 21 are indefinite because it is unclear from the language of amended independent claim 18 whether the claims do or not require an outcome in which “the concentration of DAG-1 in the exosomes from the patient” are “greater than the control concentration of DAG-1” (see c) of claim 18), such that the boundaries of the claims are not made sufficiently clear by the present claim language. Some persons of skill in the art might interpret the claims as requiring that the “comparing” of b) have a positive outcome, and that the language “identifying the patient….based on the concentration….being greater” refers to a required outcome of the claims. However, the claims may also reasonably be interpreted as not requiring such an outcome (with the claims requiring a “comparing” that need or not result in the criteria of the “identifying” being met); factors in support of this interpretation include the lack of an actual recitation of a required outcome meeting the criterion referenced in the “identifying” of claim 18, the vague language “identifying the patient….based on the concentration…”, and the above noted recitations in claims dependent from claim 1 that refer to a subject as “possibly suffering from said neurological disease/disorder” and include “wherein” language such as “wherein the concentration…is elevated” (in reference to other markers, whereas such language is lacking in the instant claims). Accordingly, as there are multiple reasonable interpretations of the claim language that impart different boundaries on what is being claimed, further clarification is required.
Claims 19 and 22 are indefinite because it is unclear from the language of amended independent claim 19 whether the claims do or not require an outcome in which “the concentration of DAG-1 in the exosomes isolated from the patient” are “greater than the control concentration of DAG-1” (see c) of claim 19), such that the boundaries of the claims are not made sufficiently clear by the present claim language. Some persons of skill in the art might interpret the claims as requiring that the “comparing” of b) have a positive outcome, and that the language “identifying the patient….based on the concentration….being greater” refers to a required outcome of the claims. However, the claims may also reasonably be interpreted as not requiring such an outcome (with the claims requiring a “comparing” that need or not result in the criteria of the “identifying” being met); factors in support of this interpretation include the lack of an actual recitation of a required outcome meeting the criterion referenced in the “identifying” of claim 19, the vague language “identifying the patient….based on the concentration…”, and the above noted recitations in claims dependent from claim 1 that refer to a subject as “possibly suffering from said neurological disease/disorder” and include “wherein” language such as “wherein the concentration…is elevated” (in reference to other markers, whereas such language is lacking in the instant claims). Accordingly, as there are multiple reasonable interpretations of the claim language that impart different boundaries on what is being claimed, further clarification is required.
It is also noted that Applicant previously proposed amending the independent claims after final to add analogous “identifying” language (see Amendment of 11 March 2026), and was advised via an Advisory action mailed 25 March 2026 that this language raised an issue under 35 USC 112(b) (although it is also noted that the language was not found to raise a new matter issue, as was noted with regard to canceled claim 23 in paragraph 6 of the Office action mailed 04 May 2026).
Claim Rejections - 35 USC § 103
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.
THE FOLLOWING INCLUDES NEW GROUNDS OF REJECTION NECESSITATED BY APPLICANT’S AMENDMENTS
Claim(s) 1, 10-11, 14-15, and 17-22 remain/are rejected under 35 U.S.C. 103 as being unpatentable over Ko et al (US 2017/0157197 A1 [08 June 2017; filed 09 December 2016]; previously cited) in view of La Salvia (University of Pavia Dissertation, 2015/2016 [available no later than 02/28/2017]; previously cited) and Schey et al (Methods 87:75-82 [31 March 2015]; previously cited), as evidenced by La Salvia-2 (IRIS Dissertation Abstract, iris.unipv.it/handle/11571/1220486 [02/28/2017]; previously cited).
It is reiterated that the claims remain indefinite for the reasons discussed above. As the claims do not clearly require a positive result of the recited “comparing” of each of the independent claims, and thus/further do not clearly require that the criteria of the “identifying” of the claims be met, the claims continue to encompass (based on one reasonable interpretation of the present language) methods in which the only wet/active method steps required are set forth in a)/b) of claim 1 and a) of claims 18/19, with the “comparing” (as well as the “identifying”, to the extent that it may be required) embracing thought/mental processes, and also constituting (an) instructional limitation(s) lacking any required functional relationship with the rest of the claimed method.
Ko et al disclose methods comprising detection of biomarkers that “can be used for prognosis of ALS disease progression”, among other applications (see entire reference, particularly the Abstract). Among the preferred biomarkers taught by Ko et al is DAG1, which is taught as being an “ALS-associated gene” (see Table 8; paragraph 179; claims 1 and 11). Ko et al disclose methods comprising quantifying ALS biomarkers, including DAG1, and classifying a patient as in need of treatment for ALS if the biomarker quantity is “sufficiently different” from a predetermined level (claim 1); with regard to (a) of instant claim 1, it is also noted that Ko et al teach, e.g., collecting patient CSF, plasma, blood, etc., for testing, which constitutes a type of “obtaining a biological sample” (see, e.g., paragraphs 98-99, 132, 139-140). Regarding the “comparing” of each of independent claim 1, 18, and 19, Ko et al also exemplify comparing “test” sample marker levels with levels in “control” samples; see, e.g., Example 2. Furthermore, the “comparing” of claims 1, 18, and 19 does not require any further active/manipulative steps beyond what is set forth in a) and b) of claim 1 and a) of claims 18/19, with that action/step as well as the “identifying” of the claims being (as noted above) instructional limitations that constitute (particularly given the indefiniteness of the claims) nonfunctional descriptive material. Further, given the lack of a clear requirement for any outcome corresponding to a diagnosis or prognosis, the preamble recitation of “diagnosing or prognosing” is interpreted as an intended use of the claimed method that need not be given patentable weight (see MPEP 2111.02) (although it is noted that Ko et al do disclose DAG-1 as a biomarker that may be applied in determining, e.g., ALS progression, as was already discussed above).
With further regard to dependent claims 10-11 and 20-22, it is reiterated that Ko et al teach the preferred disorder ALS (see above). Regarding dependent claims 14-15, the sample types taught by Ko et al for use in their methods include CSF, plasma, and blood (see, e.g., paragraphs 78-79; 83-85; 105; 126; 132); thus, Ko et al explicitly teach the use of biological samples including preferred samples recited in the claims.
Ko et al do not teach methods employing exosomes isolated from a biological sample, including extracting proteins therefrom and treating and analyzing such proteins, etc. (as recited in claims 1, 18, and 19) so as to determine the/a concentration of DAG-1 in exosomes.
La Salvia provides an overview of extracellular vesicles (including exosomes) in subjects with neurological disorders (section 8.1) - teaching that such vesicles have been shown to be present in such subjects “in a multitude of biological fluids” including blood (section 8.2) – and teaching the relevance of such vesicles in ALS specifically (section 9). Regarding a)-b) of amended claim 1, it is noted that La Salvia teach obtaining biological samples from patients and isolated exosomes therefrom (see section 8.3, particularly the “Materials and Methods”). La Salvia teach that an advantage of analysis of markers (including both protein and RNA “cargo”) within such vesicles – as compared to soluble molecules in fluids/blood – is that the markers are protected from degradation and may be “intact and functional”; additionally, La Salvia teach that such vesicles “appear to have a relatively long half-life in blood” (section 8.2, particularly the last full paragraph of the section). As it is noted that a public availability date of the La Salvia dissertation is not clear from the text of La Salvia alone, La Salvia-2 is cited as evidence that La Salvia was publicly available no later than 02/28/2017 (given the Abstract, publication date, and link provided by La Salvia-2; see entire reference).
While La Salvia teaches various techniques for analysis of exosomal/extracellular vesicle biomarkers and proteins extracted therefrom (see in particular section 9), La Salvia do not teach the use of enzyme digestion “to produce a plurality of enzyme digested peptides” and determining the concentration thereof” (as is now required by all claims), or the use of mass spectrometry in such analysis (as continues to be recited in independent claim 1).
Schey et al teach “proteomics characterization” of exosome cargo, stating that such characterization “is of significant interest because this cargo can provide clues to exosome biogenesis, targeting, and cellular effects and may be a source of biomarkers for disease diagnosis, prognosis, and response to treatment” (Abstract, and see entire reference). Schey et al teach that such analysis of exosomal proteins may achieve “both qualitative and quantitative characterization of exosomal proteins”, and Schey et al provide detailed protocols for achieving such analysis, including protocols for sample preparation and mass spectrometry (see entire reference, particularly page 78, left column regarding sample preparation and pages 78-80 regarding mass spectrometry). With particular regard to a)/b) of the independent claims, reciting the use of an enzyme to produce enzyme-digested peptides, Schey et al disclose overnight trypsin digestion (see step 5) of the “Sample preparation” of 3.1.1, left column of page 78); this disclosure of 3.1.1 also includes exosome isolation and lysis, as well as the teaching of trypsin (as is recited in dependent claim 17). Advantages taught by Schey et al for targeted peptide analysis by their methods include “highly sensitive and quantitative information on hundreds of peptides of interest in a single experiment” (page 77, right column).
In view of the teachings of La Salvia and Schey et al, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Ko et al so as to have targeted for analysis - including by enzyme digestion and mass spectrometry – proteins (including DAG-1, if/when present) obtained from exosomes isolated from samples of subjects possibly suffering from a neurological disorder and/or ALS specifically, and thereby to have performed methods meeting the requirements of the claims. An ordinary artisan would have been motivated to have isolated and analyzed target molecules contained in such exosomes by the teachings of La Salvia (noted above) regarding their advantages as stable targets of “cargo” biomarkers of such conditions (as compared to freely circulating soluble biomolecules, which are taught as being subject to degradation); further, such an artisan would have been motivated to have employed the enzyme digestion and mass spectrometry techniques of Schey et al in such analysis for any of the benefits taught by Schey et al, e.g., the benefit of achieving sensitive and quantitative information regarding many peptides of exosomal origin in a single experiment. Additionally, given the detailed guidance provided by La Salvia and Schey et al, an ordinary artisan would have had a reasonable expectation of success in performing such methods, as it is particularly again noted that Applicant’s claims do not clearly require any particular outcome regarding the status of DAG-1 in a tested subject; rather, the claims require the performance of a method sufficient to achieve determining the concentration of DAG-1 and comparing that concentration with that of a reference sample (which claim language does not in fact require any particular level (or even the presence of) DAG-1. Accordingly, all of claims 1, 10-11, 14-15, and 17-22 are prima facie obvious over the combination of Ko et al, La Salvia, and Schey et al.
The Reply of 29 July 2026 traverses the prior rejection of claims under 35 USC 103 on the following grounds.
Applicant notes that each of the independent claims has been “amended to recite an affirmative ‘identifying’ step” (Reply pages 8-9), and urges that this amendment is sufficient to overcome the prior art, as the claims now “positively require ‘identifying the patient as suffering from the neurological disorder based on the concentration of DAG-1 in the isolated patient exosomes being greater than the control concentration of DAG-1’” (Reply page 10). The Reply argues that the “identifying” now recited in the claims is entitled to patentable weight, and that the Office’s prior characterization of the claims – with “comparing” and “identifying” having been treated as non-functional descriptive material and the preamble as an intended use – does not apply to the claims as amended (Reply page 10 bridging to page 11). The Reply cites to MPEP 2111.05, noting that “where an instructional limitation, the relevant inquiry is whether there is a ‘new and nonobvious functional relationship with the [known] method’”, and urging that step (d) of amended claim 1 (equivalent to c) of amended independent claims 18-19) “bears such a relationship because the required identification depends on, and is dictated by, the specific measured elevation of exosomal DAG-1 produced by the preceding physical steps” of the claims; Applicant also again notes that the Office’s prior characterization of the “identifying” as an instructional limitation “was expressly premised on the indefiniteness of the claim” (Reply page 11).
Applicant further argues that the cited art “teaches away from the method as now claimed”, pointing to Ko et al’s teaching “that DAG-1 gene expression is increased by GM6 treatment” and description of “GM604 as modulating genes ‘by up and down regulate each gene closer to a normal range”, urging that these teaching imply “that DAG-1 is below normal in untreated ALS patients – the opposite of the elevated exosomal DAG-1 that step (d) of claim 1 requires for identifying a patient as suffering from the neurological disorder” (Reply page 11). The Reply also states that “Ko is directed to prognosis of disease progression during GM604 treatment, not diagnosis of ALS”, and notes Ko et al’s statements regarding a lack of diagnostic biomarkers for ALS (Reply page 11 bridging to page 12).
Next, Applicant argues that a reasonable expectation of success is lacking, particularly with regard to an “expectation that elevated exosomal DAG-1 would identify a patient as suffering from the neurological disorder as required by the claims” (Reply page 12).
Applicant also argues that the Office’s rationale for combining the references “rests on the generic methodological advantages of exosome analysis”, which fails to address “whether the specific step of using elevated exosomal DAG-1 to identify a neurological disorder would produce a diagnostically useful result” (Reply page 12).
Finally, Applicant argues that the specification “provides objective evidence of unexpected results commensurate with the claims as amended”, particularly urging that Example 6 and Figure 7 “show that “DAG-1 is significantly elevated in exosomes isolated from the blood serum of ALS patients relative to healthy subjects (P<0.1)”, and that this result “is unexpected in light of the cited art” (Reply page 13) (although Applicant acknowledges that the cited evidence “is specific to ALS and therefore most directly supports the ALS-specific claims….while remaining probative of the nonobviousness of the broader independent claims” (Reply page 13).
These arguments have been thoroughly considered but are not persuasive.
While the examiner agrees that each of the independent claims now recites an “identifying” step/activity, as discussed above, the present claim language does not clearly require a positive result for the “comparing” of the claims, or that the condition referenced in the “identifying” of “concentration of DAG-1 in” the patient sample is “greater than the control concentration” be met. As such, these arguments (as do most of the subsequent arguments) rely on a feature that is not a required claim limitation. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). With regard to the prior rejection being “premised on the indefiniteness of the claim”, it is also noted that the claims presently under consideration are also indefinite, as discussed above. If Applicant’s intent is to require that the claims be limited to methods in which the “comparing” actually results in a determination that DAG-1 concentration is elevated in the patient sample as compared to the healthy control sample - i.e., excluding a “comparing” of undetermined or any outcome from that which is encompassed by the claims - and in which the “identifying” actually requires such a patient, such requirements could be added to the claims. It is also noted that the issue of instructional limitations/non-functional descriptive material was addressed in the rejection that currently applies against the claims.
With respect to Applicant’s arguments regarding the cited art “teaching away” from the claims, it is reiterated that the claims as written are not clearly limited to methods requiring the opposite of what Ko et al teaches/identification of the subject as suffering from the disease. Again, this limitation is not clearly reflected in the present claim language. Additionally, regarding Applicant’s comments regarding Ko et al pertaining to progression rather than diagnosis “in the first instance”, it is noted that the claims as written also encompass “prognosing a neurological disorder”, which encompasses, e.g., conclusions regarding disease progression (and further the claims – particularly given this recitation of “prognosing”, and the use of the open transitional language “comprising” - do not exclude patients receiving treatment).
Regarding Applicant’s arguments pertaining to an alleged lack of a “reasonable expectation of success”, as well as an alleged deficiency in the “rationale to combine”, again these arguments reference and rely on a feature that is not a required claim limitation (as was already discussed above).
Finally, regarding Applicant’s arguments asserting that the specification “provides objective evidence of unexpected results”, as acknowledged by Applicant the majority of the claims are not limited to ALS, and it is also noted that the results discussed by Applicant were obtained using exosomes isolated from blood serum (which is not a limitation found in any claim). However, the primary reason this argument is not persuasive is again the fact that it relies on DAG-1 being “significantly elevated in exosomes” from the patient sample (specifically blood serum from ALS patients). As Applicant’s remarks allude to (and as is discuss in, e.g., MPEP 716.02(d)), a finding of nonobviousness based on unexpected results applies in situations when those result are commensurate in scope with what is claimed (which is not the case here, although it is noted that the primary issue is the failure of the claims to clearly required elevated DAG-1, with the sample and disease type being secondary issues).
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 DIANA B JOHANNSEN whose telephone number is (571)272-0744. The examiner can normally be reached Monday-Friday, 7:30 am-3:30 pm EST.
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/DIANA B JOHANNSEN/Primary Examiner, Art Unit 1682
