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 preliminary amendment filed 12/21/23 is acknowledged and has been entered. Claims 9, 11, 18-24, 27-29 and 31 have been amended. Claims 25-26 have been canceled. Accordingly, claims 1-24 and 27-32 are pending and under examination.
Specification
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
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 1-24 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 an a comparison to a reference level (e.g. abstract, col 2).
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 § 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 1-24 and 27-32 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for practicing the methods by using samples of whole blood, serum, plasma and cerebrospinal fluid, does not reasonably provide enablement for using any tissue or bodily fluid sample, as currently claimed. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
The factors to be considered in determining whether a disclosure would require undue experimentation include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art and, (8) the breadth of the claims. In re Wands, 8 USPQ2d, 1400 (CAFC 1988).
The specification teaches diagnosis of traumatic brain injury (TBI) by performing an assay to evaluate critical levels of ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) protein and/or GFAP protein specifically associated with TBI in blood samples of patients under testing. The instant clams broadly encompass using “a sample” to provide for the diagnosis of TBI. However, the instant specification is not found to be enabled for the methods when any type of sample is part of the invention for the following reasons. The instant specification does not provide neither enough guidance for such method of differential diagnosis, nor working examples, which would show that the claimed method was successfully practiced with any biological sample other than blood or CSF, thus, requiring undue experimentation on part of one skilled in the art to discover how to practice the claimed invention for its full scope.
The nature of the invention places it in the class of invention which the Federal Circuit has characterized as "the unpredictable arts such as chemistry and biology." Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001).
The prior art does not recognize that proteins found at certain levels in blood are also found at the exact same levels, or even be present, in any other bodily fluid or tissue. The specification does not provide any factual evidence or sound scientific reasoning to support a conclusion that specific levels of UCH-L1, for example, see 160 pg/mL as in claim 2, are present within urine, breast milk or bone tissue sample obtained from a normal subject so that these levels are used as a meaningful reference to evaluate TBI presence. Thus, Applicant has left those skilled in the art with too much undue experimentation to research and discover for themselves what particular fluid or tissue sample expresses UCH-L1 and/or GFAP in measurable amounts suitable for diagnostic purposes, as currently claimed. As such, Applicant has merely provided a starting point for research and experimentation and not a meaningful enabling disclosure of how to practice the full scope of the claimed invention.
The standard of an enabling disclosure is not the ability to make and test if the invention worked but one of the ability to make and use with a reasonable expectation of success.
A patent is granted for a completed invention, not the general suggestion of an idea and how that idea might be developed into the claimed invention. If mere plausibility were the test for enablement under section 112, applicants could obtain patent rights to “inventions” consisting of little more than respectable guesses as to the likelihood of their success. In the decision of Genentec, Inc, v. Novo Nordisk, 42 USPQ 2d 100,(CAFC 1997), the court held that:
“[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable” and that “[t]ossing out the mere germ of an idea does not constitute enabling disclosure”. The court further stated that “when there is no disclosure of any specific starting material or of any of the conditions under which a process is to be carried out, undue experimentation is required; there is a failure to meet the enablement requirements that cannot be rectified by asserting that all the disclosure related to the process is within the skill of the art”, “[i]t is the specification, not the knowledge of one skilled in the art, that must supply the novel aspects of an invention in order to constitute adequate enablement”.
The instant specification is not enabling because one cannot follow the guidance presented therein and practice the full scope of the claimed methods without first making a substantial inventive contribution to perfect the method and complete the invention.
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.
Claim 23 is 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.
Claim 23 the recitation “any subject” is vague and indefinite because it is unclear if the applicant is referring to the human subject of claim 1 or if the applicant intends another subject. Please clarify.
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 1-24, 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 further in view of Blankenberg et al (US 2006/0105419).
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, 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).
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 and Blankenberg et al as applied to claims 1-24, 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 and Datwyler et al.
McQuiston et al., Shinoda et al and Datwyler et al. 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.
Conclusion
No claims are allowed.
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