DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
The present application, filed on October 27, 2023, is a Divisional of 18/139,803, filed on April 26, 2023, which claims priority to U.S. Provisional Patent Application No. 63/416,502, filed on October 15, 2022.
Claim Status
Claims 1 and 2 are currently pending and under examination.
Drawings
The drawings filed February 22, 2024 are acceptable.
Claim Rejections - 35 USC § 112(b)-Indefiniteness
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.
Claims 1 and 2 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 1 recites “identifying a traumatic brain injury in a patient by detecting… the expression of one or more… miRNA biomarkers…”. It is unclear how the “identifying” and “detecting” steps are connected, as “detecting” appears to encompass: a) detecting the presence/absence of the miRNA(s), b) detecting (an) expression level(s) of the miRNA(s) that exceed a particular predetermined threshold or limit of detection or limit of quantitation of any particular assay (e.g. qPCR, PCR, LAMP, Northern blot), and c) detecting (an) expression level(s) of the miRNA(s) relative to a particular control (e.g. same patient before injury, non-injured control, a population average, or an internal/external nucleic acid control). Therefore, it is not clear whether the “detecting” step requires simply the detection of the presence/absence of expression of the claimed miRNA or miRNAs, or something more, such as detecting a change in the expression of the claimed miRNA or miRNAs compared to some unspecified value, standard, or control.
The term “the traumatic brain injury is detected by an increase in the expression of [the combination of all of the recited miRNAs]” in claim 2 is a relative term which renders the claim indefinite. The term “an increase” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
It is unclear to what the expression of the recited miRNAs is to be compared. As presently claimed, it is unclear whether the “increased” miRNA expression must be measured relative to an internal control RNA, an external “spike-in” standard, a predetermined threshold, a predetermined reference value, or a control sample collected from: a) the same patient prior to injury, b) an uninjured control patient, or something else. Furthermore, it is unclear whether the expression must be “increased” relative to this comparison by some absolute amount (i.e. 1 more) or by some relative amount (i.e. two-fold), or some other measure.
Claim 1 recites “treating the patient for the traumatic brain injury by administering one or more of… removal from physical activity”. Because the “treating” step encompasses embodiments wherein the process user is directed to perform “removal from physical activity” (i.e. doing nothing), it is unclear whether the “treating” step is required by the claim, or is an optional step.
Claim 2 is also rendered indefinite because of its dependence from, and thus incorporation of, the indefinite limitations of claim 1.
Claim Rejections - 35 USC § 101
Claims 1 and 2 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter.
35 U.S.C. 101 requires that to be patent-eligible, an invention (1) must be directed to one of the four statutory categories, and (2) must not be wholly directed to subject matter encompassing a judicially recognized exception. M.P.E.P. 2106. Regarding judicial exceptions, “[p]henomena of nature, though just discovered, mental processes, and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work.” Gottschalk v. Benson, 409 U.S. 63,67 (1972); see also M.P.E.P. 2106, part II.
Based upon consideration of the claims as a whole, as well as consideration of elements/steps recited in addition to the judicial exceptions, the present claims fail to meet the elements required for patent eligibility.
Step 1
The claimed invention is directed to a process that involves a natural principle and judicial exceptions.
Step 2A Prong I
The claims are taken to be directed to a natural phenomenon and abstract ideas.
Claim 1 is directed to a method for treating traumatic brain injury comprising: (a) identifying a traumatic brain injury in a patient by detecting the expression of one or more of a group of miRNAs in a fluid obtained from the patient; and (b) treating the patient for the traumatic brain injury by administering one or more of: acetaminophen, a therapeutic to reduce cerebral swelling, sedation, and removal from physical activity.
Claim 1 is directed to a process that involves the judicial exception of a law of nature/natural phenomenon (i.e. the natural correlation of the expression of a particular miRNA or miRNAs and the presence of a traumatic brain injury in the patient). It is noted that the treatment step encompasses “removal from physical activity” (i.e. no treatment is administered to the patient, “doing nothing”), and therefore, is not required by the claim.
Claim 2 depends from claim 1 and further requires “the traumatic brain injury is detected by an increase in the expression of [all of the recited miRNAs]”. Therefore, claim 2 further requires a comparison to some unspecified control to ascertain whether the expression of the recited miRNAs are “increased”.
A comparison to a control is an abstract idea (See M.P.E.P 2106.04(a)(III)(A); claims to “comparing BRCA sequences and determining the existence of alterations,” wherein the claims cover any way of comparing BRCA sequences such that the comparison steps can practically be performed in the human mind, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 763, 113, USPQ2d 1241, 1246 (Fed. Cir. 2014).
A correlation that preexists in the human is an unpatentable phenomenon. The association between the level or amount or expression of a naturally occurring miRNA or miRNAs and the presence of a traumatic brain injury is a law of nature/natural phenomenon. The “detecting” step recited by the claims is a data gathering step necessary to perform the method. Furthermore, as described above, the treatment step encompassing “administering… removal from physical activity” does not require the process user to do anything in light of the natural correlation and/or comparison to control. Therefore, the positively recited method steps amount to no more than an “instruction to apply the natural law”. Even if the steps require something more, such as to verbalize the discovery of the natural law, this mere verbalization is not an application of the natural law to a new and useful end. These steps fail to provide the “practical assurance” sought by the Prometheus Court that the “process is more than a drafting effort designed to monopolize the law of nature itself”.
Step 2A Prong II
The judicial exceptions are not integrated into a practical application of the exceptions. The claims do not recite any additional elements that integrate the judicial exceptions into a practical application of the exceptions.
While claim 1 recites “identifying… by detecting… the expression…”, and claim 2 recites “detect[ed] by an increase in the expression…”, these steps are not integrations of the exceptions into a practical application. Rather, these steps are extra-solution data gathering steps required to perform the claimed method.
Claim 1 recites “treating the patient for the traumatic brain injury by administering one or more of acetaminophen, a therapeutic to reduce cerebral swelling, sedation, and removal from physical activity”. This step does not integrate the exceptions into a practical application at least because: i) the treatment step does not require the process user to do anything in embodiments wherein the treatment is “administering… removal from physical activity”, and is therefore the “treatment” step is not required under the broadest reasonable interpretation of the claims, and the “therapeutic to reduce cerebral swelling” is extremely generic and encompasses any conceivable treatment known in the art including, for example, administration of non-steroidal anti-inflammatory drugs, ice packs, etc., and therefore does not require any particular therapy.
Step 2B
The second step of Alice involves determining whether the remaining elements, either in isolation or combination with the other non-patent eligible elements, are sufficient to “transform the nature of the claims into a patent eligible application” Alice, 134 S. Ct. at 2355 (quoting Mayo, 132 S. Ct at 1297).
The claims are not sufficiently defined to provide a method which is significantly more than a statement of a natural principle for at least these reasons:
The claims do not add a specific limitation other than what is well-understood, routine, and conventional in the field.
Steps directed to “detecting… the expression of one or more of [a group of miRNA biomarkers]” are mere data gathering steps that amount to extra solution activity to the judicial exception. The claims do not require any particular methodology for the detecting step, and thus encompass any method of detecting the recited miRNAs known in the art.
Detecting differential expression of each of the recited miRNAs in fluids obtained from patients after receiving a traumatic brain injury are well known in the art.
The prior art, for example, Van Keuren-Jensen et al., US 2018/0258483 A1, teach measuring elevated expression of miR-1287-5p in plasma from patients following a traumatic brain injury (Van Keuren-Jensen et al., paragraph 0025, tables 1, 10, and 39). Furthermore, Hicks et al., US 2020/0277676 A1, teach miR-1273e and miR-6873-3p are upregulated in saliva from patients following a traumatic brain injury (Hicks et al., tables 32A and 3, respectively). Finally, Belli et al., WO 2020/165863 A2, teach miR-1273h is upregulated in saliva samples from patients with concussions relative to samples from patients with musculoskeletal injuries (i.e. a control group) (Belli et al., Table 3A).
Steps directed to “treating the patient… by administering one or more of acetaminophen, a therapeutic to reduce cerebral swelling, sedation…” (i.e. steps that require administering a drug) are likewise well-known, routine, and conventional in the art. For example, Belli et al. teach therapies for alleviating traumatic brain injuries include administering drugs to treat cerebral swelling such as mannitol and hypertonic saline and/or other neuroprotective measures, such as avoidance of hypertensive resuscitation and the use of sedation (Belli et al., paragraph 0060). Additionally, Belli et al. teach removing a patient with a traumatic brain injury from physical activity (Belli et al., paragraph 0054).
Finally, Kiser et al., “UAMS Traumatic Brain Injury Guidelines 2019”, teach administering acetaminophen as a first-line (i.e. routine) pharmacologic treatment for pain following a traumatic brain injury (Kiser et al., page 4, section “D. Pharmacologic Treatment”).
Additionally, the claims do not require the use of any particular non-conventional reagents to accomplish the “detecting” or “treating” steps.
For these reasons, the claims are rejected under section 101 as being directed to non-statutory subject matter.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim 1 is rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Belli et al., WO 2020/165863 A2 (published August 20, 2020).
Regarding claim 1, Belli et al. teach identifying patients with traumatic brain injuries by determining a level of at least one miRNA biomarker in a saliva sample from a subject (Belli et al., Abstract), and that one such miRNA biomarker that is upregulated in patients having concussions (i.e. a traumatic brain injury) relative to uninjured patients or patients with musculoskeletal injuries (i.e. control groups) is hsa-miR-1273h (Belli et al., Table 3A). Belli et al. further teach treating patients identified as having traumatic brain injuries by removing a patient with a traumatic brain injury from physical activity (Belli et al., paragraph 0054) and/or administering drugs to treat cerebral swelling such as mannitol and hypertonic saline and/or other neuroprotective measures, such as avoidance of hypertensive resuscitation and the use of sedation (Belli et al., paragraph 0060).
Therefore, Belli et al. teach all of the positively recited method steps required by claim 1.
Claim 1 is rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Van Keuren-Jensen et al., US 2018/0258483 A1 (published September 13, 2018).
Regarding claim 1, Van Keuren-Jensen et al. teach measuring elevated expression of miR-1287-5p in plasma from patients following a traumatic brain injury (Van Keuren-Jensen et al., paragraph 0025, tables 1, 10, and 39). Van Keuren-Jensen et al. further teach determining the fitness of a subject for participating in an activity based upon a risk of further, more serious, head injuries determined by the expression levels of marker miRNAs (i.e. removal from physical activity) (Van Keuren-Jensen et al., abstract).
Therefore, Van Keuren-Jensen et al. teach all of the positively recited method steps required by claim 1.
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.
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 and 2 are rejected under 35 U.S.C. 103 as being unpatentable over Van Keuren-Jensen et al., US 2018/0258483 A1 (published September 13, 2018) in view of Belli et al., WO 2020/165863 A2 (published August 20, 2020), Hicks et al., US 2020/0277676 A1 (published September 3, 2020) and Kiser et al., “UAMS Traumatic Brain Injury Guidelines 2019” (Published May 2019).
Regarding claim 1, Van Keuren-Jensen et al. teach measuring elevated expression of miR-1287-5p in plasma from patients following a traumatic brain injury (Van Keuren-Jensen et al., paragraph 0025, tables 1, 10, and 39) and determining the fitness of a subject for participating in an activity based upon a risk of further, more serious, head injuries determined by the expression levels of marker miRNAs (i.e. removal from physical activity) (Van Keuren-Jensen et al., abstract).
Regarding claim 2, Van Keuren-Jensen et al. teach detecting a combination of marker miRNAs with increased expression following traumatic brain injury. However, Van Keuren-Jensen et al. do not teach increased expression of hsa-miR-1273e, hsa-miR-1273h-5p, or hsa-miR-6873-3p in their cohort.
However, Hicks et al. teach miR-1273e and miR-6873-3p are upregulated in saliva from patients following a traumatic brain injury (Hicks et al., tables 32A and 3, respectively) and Belli et al. teach miR-1273h is upregulated in saliva samples from patients with concussions relative to samples from patients with musculoskeletal injuries (i.e. a control group) (Belli et al., Table 3A).
Furthermore, Hicks et al. teach that combinations of miRNA markers perform better at identifying traumatic brain injuries with increasing numbers of significant miRNAs comprising the panel of markers (Hicks et al., figure 12 and paragraph 0305).
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Regarding the alternative treatment steps recited by claim 1 and included in claim 2, Belli et al. teach treating patients identified as having traumatic brain injuries by removing a patient with a traumatic brain injury from physical activity (Belli et al., paragraph 0054) and/or administering drugs to treat cerebral swelling such as mannitol and hypertonic saline and/or other neuroprotective measures, such as avoidance of hypertensive resuscitation and the use of sedation (Belli et al., paragraph 0060). Similarly, Kiser et al. teach administering acetaminophen as a first-line (i.e. routine) pharmacologic treatment for pain following a traumatic brain injury (Kiser et al., page 4, section “D. Pharmacologic Treatment”).
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to have combined the methods comprising detecting the expression of miRNA biomarkers for identifying traumatic brain injuries in fluids obtained from a patient taught by Van Keuren-Jensen et al. (miR-1287-5p), Belli et al. (miR-1273h), and Hicks et al. (miR-1273e and miR-6873-3p) and treating the patient for the traumatic brain injury by removing a patient with a traumatic brain injury from physical activity (Belli et al., paragraph 0054) and/or administering drugs to treat cerebral swelling such as mannitol and hypertonic saline and/or other neuroprotective measures, such as avoidance of hypertensive resuscitation and the use of sedation as taught by Belli et al., (Belli et al., paragraph 0060) and/or administering acetaminophen as a first-line (i.e. routine) pharmacologic treatment for pain following a traumatic brain injury as taught by Kiser et al. (Kiser et al., page 4, section “D. Pharmacologic Treatment”).
The ordinary artisan would have been motivated to combine the miRNA biomarkers and treatments taught by Van Keuren-Jensen et al., Belli et al., Hicks et al., and Kiser et al. because each of these references teach measuring increased expression of each of the aforementioned miRNAs is indicative of a traumatic brain injury and because Hicks et al. teach that panels of miRNA biomarkers for traumatic brain injury exhibit increasing performance with increasing numbers of miRNA biomarkers simultaneously measured (Hicks et al., figure 12). Therefore, the ordinary artisan would have expected methods comprising measuring a combination of multiple miRNA biomarkers would have performed better than measuring single miRNA biomarkers in isolation.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ZACHARY MARK TURPIN whose telephone number is (703)756-5917. The examiner can normally be reached Monday-Friday 8:00 am - 5:00 pm.
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/Z.M.T./Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682