DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the claims
The amendment filed 07/28/26 is acknowledged and has been entered. Claims 1, 9 and 23-24 have been amended. Claim 2 has been canceled. Claims 25-26 were previously canceled. Accordingly, claims 1, 3-24 and 27-32 are pending and under examination.
Withdrawn Rejections
All rejections of claims not reiterated herein, have been withdrawn.
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.
Claims 1, 3-24 and 27-32 are rejected under 35 U.S.C. 101 because the claimed invention is directed to abstract ideas and/or to laws of nature/natural phenomena without significantly more.
The U.S. Patent and Trademark Office recently revised the MPEP with regard to § 101 (see the MPEP at 2106). Regarding the MPEP at 2106, in determining what concept the claim is “directed to,” we first look to whether the claim recites:
(1) any judicial exceptions, including certain groupings of abstract ideas (i.e., mathematical concepts, certain methods of organizing human activity such as a fundamental economic practice, or mental processes); and
(2) additional elements that integrate the judicial exception into a practical application (see MPEP § 2106.05(a)-(c), (e)-(h)).
Only if a claim (1) recites a judicial exception and (2) does not integrate that exception into a practical application, do we then look to whether the claim contains an “‘inventive concept’ sufficient to ‘transform’” the claimed judicial exception into a patent-eligible application of the judicial exception. Alice, 573 U.S. at 221 (quoting Mayo, 566 U.S. at 82). In so doing, we thus consider whether the claim:
(3) adds a specific limitation beyond the judicial exception that is not “well-understood, routine, conventional” in the field (see MPEP § 2106.05(d)); or
(4) simply appends well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception.
See MPEP 2106.
ELIGIBILITY STEP 2A: WHETHER A CLAIM IS DIRECTED TO A JUDICIAL EXCEPTION
Step 2A, Prong 1
The claims are directed to a naturally occurring correlation between the levels of the recited biomarkers in a subject with supermild or mild traumatic brain injury (TBI) compared to a reference level.
Step 2A, Prong 2
The additional elements of performing at least one assay to measure the level of GFAP and/or UCH-L1 and comparing to a reference does not apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception.
Also, with respect to the recitations “determining that the subject has sustained a supermild TBI when the level of GFAP in the sample is less than a reference level….” (as recited in claim 1) and “differentiating mild TBI from supermild TBI based upon whether the level of GAP in the sample is equal to or less than a reference level of GFAP….” (as recited in claims 4 & 13). The “determining” and “differentiating” statements at best articulates the judicial exception, amounting only to a general instruction to apply or use the judicial exception. This could read on mental activity being performed solely in a practitioner’ head, e.g. A mental appreciation of levels of the recited biomarkers being correlated with mild or supermild TBI. No active method steps are invoked or clearly required; the “determining” and “differentiating” statements do not include any activity that would constitute a practical application, i.e. steps that apply, rely on or use the natural principle in a manner such that the claims amount to significantly more that the natural principal itself.
ELIGIBILITY STEP 2B: WHETHER THE ADDITIONAL ELEMENTS CONTRIBUTE AN "INVENTIVE CONCEPT"
Further, the additional elements of the claims are recited with a high level of generality and do not apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception. (the active method steps/limitations recited in addition to the judicial exceptions themselves) and do not add significantly more to the judicial exception(s).
As shown by both McQuiston et al (US 11,016,105) it is well known routine and conventional in the art to obtain a sample from a subject and to measure the levels of GFAP and UCH-L1 and make a comparison to a reference level (e.g. abstract, col 2).
With respect to the “treating the subject determined as having a supermild traumatic brain injury with a supermild traumatic brain injury treatment” as recited in claim 1. Although the claim invokes treating the subject the claim currently recites “determining that the subject has sustained a supermild TBI when the level of the sample is less than a reference…” The recitation of “when” allows for the scenario when the level is above a reference level indicating the subject does not have a supermild TBI and thus a supermild treatment would not be applied to this subject. Therefore, this scenario does not recite something significantly more than the judicial exception. Also, the claim currently recites an intervention step that is generic and allows for anything already known and conventional such as rest or bed rest wherein no intervention is actually performed on the subject. Therefore, the claims as currently recited do not recite something significantly more than the judicial exception.
It does not appear to be the case that the active steps recited, which are performed in order to gather the data or perform the assay, are steps recited or performed in an unconventional or non-routine way, such to provide an inventive concept under step 2B.
The claimed limitations as currently presented fail to recite limitations that add a feature that is more than well understood, conventional or routine in the field of diagnostics and biochemical assay methodologies.
For all of these reasons, the claims fail to include additional elements that are sufficient to either integrate the judicial exception(s) into practical application(s) thereof, or amount to significantly more than the judicial exception(s).
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.
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.
Claims 1, 3-24, 27-28 and 31-32 are rejected under 35 U.S.C. 103 as being unpatentable over McQuiston et al (US 11,016,105) in view of Shinoda et al (Neurol Med Chir 57, 2017, pages 199-209) and Blankenberg et al (US 2006/0105419) and further in view of Mayo Clinic (Team approach to treating traumatic brain injuries, March 17, 2021, Mayo Clinic Health System, pages 1-6).
McQuiston et al discloses methods for aiding in the diagnosis and evaluation of a human subject that has sustained or may have sustained an injury to the head and determining whether the subject has sustained traumatic brain injury by detecting or measuring UCH-L1 and GFAP in a sample from the subject (e.g. abstract, col 2- col 3, col 42, lines 13-29, col 47-48). McQuiston et al discloses that the sample can be obtained at about 12 hours, or 24 hours (col 2, line 56 – col 3, line 28). McQuiston et al discloses evaluating the subject for mild, moderate or severe traumatic brain injury (TBI) and discriminating between mild, moderate and severe TBI (e.g. col 8, lines 48-65, col 9, line 26-34, col 12, lines 9-31, col 42, lines 13-29, col 47-48). McQuiston et al discloses that the sample can be whole blood, serum, plasma or cerebrospinal fluid (e.g. col 9, lines 4-24, col 12, lines 33-45). McQuiston et al discloses that the subject can have GCS scores of 13-15 for mild TBI (col 40, lines 61-65) (as disclosed by Applicant on page 35, paragraph 100 supermild has a score of 15). McQuiston et al discloses comparing the level of the biomarkers to that of a reference and that lower levels indicate the subject has mild TBI (e.g. col 42, lines 13-29). McQuiston et al discloses that the markers can be measured by immunoassay wherein a GFAP-capture antibody and a GFAP detection antibody bind to the GFAP and a UCH-L1 capture antibody and detection antibody are used to detect the UCH-L1 (e.g. col 8). McQuiston et al discloses performing the tests at 2 weeks on samples obtained at 2 weeks (e.g. col’s 137-138). McQuiston et al discloses that the sample can be obtained after physical shaking, blunt impact, ingestion or exposure to a chemical toxin, or from a subject that suffers from an autoimmune disease, metabolic disorder, a brain tumor, hypoxia, a virus, meningitis, hydrocephalus or combinations thereof (col 5). McQuiston et al discloses the method can be carried out on any subject without regard to the subjects clinical condition (e.g. col 5). McQuiston et al discloses that the subject can be treated or monitored (e.g. col 8, lines 48-67). McQuiston et al discloses the assay used can be a single molecule detection assay or a point-of-care assay (e.g. col 5, lines -55).
McQuiston et al differs from the instant invention in failing to teach determining supermild TBI and distinguishing supermild from mild TBI.
Shindoa et al teaches that mild TBI can be subgrouped into super mild TBI and that these subjects may be subjects with no loss of consciousness, loss of memory for events immediately before or after accident, alteration in mental state at the time of the accident, nor focal neurologic deficits that may or may not be transient (e.g. pgs 200-201).
It would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to incorporate super mild TBI subjects such as taught by Shindoa et al into the method of McQuiston et al because Shindoa et al shows that these subjects have sustained a TBI but may not have lost consciousness but are a subgroup of mild TBI. Thus, one of ordinary skill in the art would have a reasonable expectation of success incorporating super mild TBI subjects such as taught by Shindoa et al into the method of McQuiston et al.
McQuston et al and Shindoa et al differ from the instant invention in failing to teach the specific references levels (cutoffs) for the differentiation of mild TBI and supermild TBI.
However, it was recognized in the prior art that the sensitivity and specificity is a measure of the accuracy of a test, reflecting the number (if any) of false positives and false negatives. Furthermore, sensitivity and specificity may be adjusted by adjusting the value of a threshold or cutoff value, above which (or below which, depending on how a marker changes with the disease) the test is considered to be indicative of one state or condition (e.g., diseased) and below which the test is considered to be indicative of another state or condition (e.g., non-diseased). See Blankenberg et al at [0007], [0028], [0084]. Accuracy need not be 100%; however Blankenberg et al indicates that particularly preferred would be where both the sensitivity and specificity are at least about 75%, more preferably at least about 80%, even more preferably at least about 85%, still more preferably at least about 90%, and most preferably at least about 95% [0028].
The teachings of Blankenberg et al indicate that the sensitivity and specificity of a diagnostic test was known to be a result-effective variable, impacting the number of individuals who are correctly diagnosed with disease. Furthermore, the teachings of Blankenberg et al indicate that it was known in the prior art to optimize tests for desired levels of sensitivity and specificity, by selecting appropriate threshold or cutoff values.
Therefore, it would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to incorporate comparison to a reference and to arrive at the claimed invention by optimizing cutoff levels in order to achieve a desired sensitivity and specificity as claimed (i.e. the specific cutoff levels), given that such percentages were recognized in the art to be particularly preferred for diagnostic tests. One skilled in the art would have been motivated to select such levels of sensitivity and specificity out of the course of routine optimization, given that these measures of test accuracy were recognized in the prior art to be result-effective variables that impact the number of false negatives and false positives for the test. It has long been settled to be no more than routine experimentation for one of ordinary skill in the art to discover an optimum value of a result effective variable. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation.” Application of Aller, 220 F.2d 454,456, 105 USPQ 233, 235-236 (C.C.P.A. 1955). “No invention is involved in discovering optimum ranges of a process by routine experimentation .” Id. At 458,105 USPQ at 236-237. The “discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.” Application of Boesch, 617 F.2d 272,276, 205 USPQ 215, 218-219 (C.C.P.A. 1980).Finally, one skilled in the art would have had a reasonable expectation of success in arriving at the claimed cutoffs since means of achieving desired sensitivity and specificity were known, namely by selecting an appropriate threshold or cutoff level (as taught by Blankenberg et al).
McQuston et al., Shindoa et al and Blankenberg differ from the instant invention in failing to teach treating the subject having the supermild traumatic brain injury.
Mayo Clinic teaches that a mild injury to the brain is still a serous injury that requires prompt attention and that a person does not have to lose consciousness to have a mild brian injury. Mayo Clinic teaches that most mild traumatic brain injuries usually require not treatment other than rest and over-the-counter pain relievers (e.g. page 2).
It would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to incorporate treatment such as taught by Mayo Clinic for the diagnosed subject in the modified method of MQuston et al because Mayo Clinic shows that a mild injury to the brain is still a serious injury that requires prompt attention and that most mild traumatic brain injuries usually require not treatment other than rest and over-the-counter pain relievers. Thus, one of ordinary skill in the art would have a reasonable expectation of success incorporating a treatment such as taught by Mayo Clinic for the diagnosed subject in the modified method of MQuston et al.
With respect to claims 31-32 as currently recited. The combination of McQuiston et al., Shinoda and Blakenberg teach immunoassays, single molecule detection assays and point-of-care assays consonant to the instantly recited claims and therefore, absent evidence to the contrary it is deemed that the assays would be performed in about 10 to about 20 minutes and about 15 minutes as claimed.
Claims 29-30 are rejected under 35 U.S.C. 103 as being unpatentable over McQuiston et al in view of Shinoda et al., Blankenberg et al and Mayo Clinic as applied to claims 1, 3-24, 27-28 and 31-32 above, and further in view of Datwyler et al (US 2018/0106818).
See above for the teachings of McQuiston et al., Shinoda et al., Blankenberg et al and Mayo Clinic
McQuiston et al., Shinoda et al., Blankenberg et al and Mayo Clinic differ from the instant invention in failing to teach the amount of sample is about 20 uL.
Datwyler et al shows that it is known and conventional in the art to use a volume of sample of less than 20 uL in an immunoassay for the detection of a biomarker (e.g. para’s 0025, 0029, 0045, 0047, 0159).
It would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to incorporate a volume of sample such as taught by Datwyler et al into the modified method of McQuiston et al because McQuiston et al is generic with respect to the amount of sample and Datwyler et al shows that it is known and conventional in the art to use a volume of less than 20 uL. Thus, one of ordinary skill in the art would have a reasonable expectation of success incorporating a volume of sample such as taught by Datwyler et al into the modified method of McQuiston et al.
Response to Arguments
Applicant's arguments filed 09/08/26 have been fully considered but they are not persuasive.
101 Rejections:
Applicant argues that the claims recite an active treatment step that integrates any judicial exception into a practical application.
This argument is not found persuasive because although the claim invokes treating the subject the claim currently recites “determining that the subject has sustained a supermild TBI when the level of the sample is less than a reference…” The recitation of “when” allows for the scenario when the level is above a reference level indicating the subject does not have a supermild TBI and thus a supermild treatment would not be applied to this subject. Therefore, this scenario does not recite something significantly more than the judicial exception. Also, the claim currently recites an intervention step that is generic and allows for anything already known and conventional such as rest or bed rest wherein no intervention is actually performed on the subject. Therefore, the claims as currently recited do not recite something significantly more than the judicial exception.
Applicant argues that the combination of specific sample type, specific time window, specific thresholds and specific treatment is not well-understood, routine and conventional.
This argument is not found persuasive because the claims are directed to a method that starts with supermild traumatic brain injury biomarkers determined in a whole blood, serum or plasma sample which are naturally occurring markers found in naturally occurring samples and thus the claims are directed to a matter that is naturally occurring. Ariosa Diagnostics, Inc. v. Sequenom, Inc. (Fed Cir, 2014-1139, 2014, 06/12/15). Further, with respect to thresholds. Blankenberg et al (supra) shows that the establishment of thresholds are well known, routine and conventional and a specific value of a threshold would not necessarily render a claim patent eligible as was seen in the case of Mayo v. Prometheus (which also recited a specific threshold value). Also, the specific time windows as argued are actually a component of the natural correlation.
103 Rejections:
Applicant argues that McQuiston does not use the term “supermild” anywhere in the specification and McQuiston does not partition mild TBI into subgroups.
This argument is not found persuasive because the Examiner has not relied upon McQuiston for teaching supermild TBI but rather has relied upon Shinoda for showing that it is known in the art that mild TBI can be subgrouped into supermild subjects. Thus, the Applicant is arguing McQuiston individually. 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). Further, although McQuiston et al may not specifically state supermild MCQuiston et al discloses that the subject can have GCS scores of 13-15 for mild TBI (Col 40, lines 61-65) (and as disclosed by Applicant on page 35, paragraph 100 of the current specification supermild has a score of 15) and Shinoda shows that subjects that fall within a GCS score of 13-15 and do not have loss of consciousness, loss of memory for events immediately before of after accident, alteration in mental state at the time of accident, nor focal neurologic deficits that may or may not be transient would be classified as supermild. Thus, Shinoda provides the knowledge and motivation to differentiate a mild TBI and a supermild TBI.
Applicant argues that Shinoda discloses no biomarker, no cutoff and no biomarker based method.
This argument is not found persuasive because the Examiner has not relied upon Shinoda for the biomarker, cutoff or biomarker based method. Thus, the Applicant is arguing Shinoda individually. 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).
Applicant argues that Shinoda's exploratory description of "super mild TBI" refers to subjects "with a GCS score of 13-15 points, but with no loss of consciousness, loss of memory for events immediately before or after accident, alteration in mental state at the time of the accident, nor focal neurologic deficits" (Shinoda, p. 201, left column). The application, by contrast, defines "supermild TBI" specifically as "a subclass or a subtype of mild TBI wherein a subject has a Glasgow Coma scale number of 15" (Specification, "Supermild TBI" definition, p. 34). The application's definition is more specific and turns on the GCS score, not on the absence of the four American Congress of Rehabilitation Medicine criteria as in Shinoda.
This argument is not found persuasive because Applicant’s definition goes on to state that a subject with a supermild TBI will exhibit less structural damage and less functional impairment that a subject having mild TBI. This is exactly what Shinoda is teaching A GCS score of 15 and no loss of consciousness, loss of memory for events immediately before or after accident, alteration in mental state at the time of the accident, nor focal neurologic deficits (i.e. less structural and functional impairment. The Applicant has not specifically provided a different in the definitions but rather appears to have not stated the entire definition provided by the Applicant and one of ordianary skill would understand that the teachings of Shinoda combined with the other references read on the instant “supermild” subject and how to determine such a subject.
Applicant argues that Blankenberg does not supply the specific cutoff recited in amended claim 1.
This argument is not found persuasive because the Examiner agrees that Blankenberg does not specifically recite a cutoff of “about 55pg/mL” and about 160 pg/mL” but rather shows that it is known and conventional in the art of diagnostic assay to establish a specific cutoff and that the test is known to be a result-effective variable and known to optimize test for desired levels of sensitivity and specificity and therefore it would have been obvious to optimize the levels in the modified method of McQuiston to arrive at the recited specific cutoff levels for the differentiation of mild and supermild TBI. The Applicant is arguing the reference individually and not considering the combination of McQuiston, Shinoda, Blankenberg and Mayo Clinic. 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).
Conclusion
No claims are allowed.
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 GARY W COUNTS whose telephone number is (571)272-0817. The examiner can normally be reached M-F 7:00-4:00.
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/GARY COUNTS/ Primary Examiner, Art Unit 1678
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