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 .
Election/Restrictions
Applicant’s response to the restriction/ election requirement from 7/9/2026 is acknowledged. Applicant has made the following election without traverse.
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The restriction/ election requirement is hereby MADE FINAL. Claims 1, 2, 7, 9, 10, 12 and 14 are pending, and have been examined herewith to the extent of Applicant’s elected species.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 2, 7, 9, 10, 12 and 14 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 1-12 are vague and indefinite and subject to many different interpretations. Claim 1 is directed to a method of treating a trauma patient. The claims are vague and indefinite, because “trauma” is defined so broadly in the specification, that it is potentially open to a limitless number of diseases and medical treatments, without a clear boundary what they are. The specification provides: “[0037] As used herein, a “trauma” can refer to an incident or other traumatic event that causes physical harm. In some embodiments the trauma can be clinical trauma, physical trauma, or combat trauma. In some embodiments, a trauma can include a clinical trauma (e.g., injury, infection, secondary disease, medical procedures, surgery, inflammation, tissue damage, medical treatment, or combinations thereof).”. As can be seen from this paragraph “trauma” is defined that it “can refer to”, but not necessarily that it “refers to”—i.e. “can” only produces a possibility”—that the trauma can be “incident or other traumatic event that causes physical harm”. But as the second sentence provides, and as claim 12 recites too (“12. The method of claims 1, wherein the trauma comprises clinical trauma, physical trauma, or combat trauma, wherein the clinical trauma comprises surgery, injury, tissue damage, infection, inflammation, pain, medical treatment, secondary disease, or combinations thereof.”), the trauma can also be defined to be even just “inflammation”, or just “pain”, or any “medical treatment”, or any “secondary disease”, or “combinations thereof”. This opens the claims, and particularly claim 1, as further exemplified by claim 12, to a very vaguely defined and potentially limitless number of diseases, conditions and medical treatments.
Claim 1 is further vague and indefinite, because the claim does not even require treating trauma per se. It solely provides “A method of treating a trauma patient”, but that only provides a reference vis-à-vis the patient, that it has trauma. The claim itself does not what disease in the trauma patient is being treated per se.
Claim 1 is further vague and indefinite, because a search of the art reveals that while paroxetine is both an SSRI and a GRK2 inhibitors, other SSRIs, e.g. citalopram, escitalopram, fluoxetine, paroxetine, sertraline are only known to be SSRIs, but are not known to inhibits GRK2. Yet, Applicant’s specification broadly groups these SSRIs with the GRK2 inhibitors encompassed by the claims.
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(Specification, p. 17).
In the interest of compact prosecution, the Examiner interprets claim 1 as directed to:
1. A method of treating trauma in a trauma patient, comprising:
(a) administering a HDAC inhibitor to the trauma patient, wherein the HDAC inhibitor comprises vorinostat, panobinostat, belinostat, romidepsin, chidamide, valproic acid, tacedinaline, mocetinostat, abexinostat, practinostat, resminostat, givinostat, quisinostat, HBI-8000, or combinations thereof; and
(b) administering a GRK2 inhibitor to the trauma patient, wherein the GRK2 inhibitor comprises paroxetine, GSK180736A, CMPD101, CMPD103, or combinations thereof,
wherein the trauma is the result of an incident or other traumatic event that causes physical harm.
Claim 9 recites the limitation "the GRK2 inhibitor is paroxetine" in lines 1-2. There is insufficient antecedent basis for this limitation in the claim. Claim 9 depends from claim 1, but claim 1 does not recite “paroxetine” in its list of GRK2 inhibitors. Specifically, claim 1 recites: “1. (Currently Amended) A method of treating a trauma patient, comprising: (a) administering a HDAC inhibitor to the trauma patient, wherein the HDAC inhibitor comprises vorinostat, panobinostat, belinostat, romidepsin, chidamide, valproic acid, tacedinaline, mocetinostat, abexinostat, practinostat, resminostat, givinostat, quisinostat, HBI-8000, or combinations thereof; and (b) administering a GRK2 inhibitor to the trauma patient, wherein the GRK2 inhibitor comprises a selective serotonin reuptake inhibitor, GSK180736A, CMPD101, CMPD103, or combinations thereof.”
It is noted that Applicant’s election of species provides in relevant part that Applicant elects as a species of a GRK2 inhibitor- “an SSRI, more specifically paroxetine”. To that end, there is a recitation in claim 1 from which claim 9 depends that the GRK2 inhibitor can be, inter alia, an SSRI. It is further noted that the mechanism of action of paroxetine is not solely that of a selective serotonin reuptake inhibitor, but that it is also known to have other pharmacological effects as well. (see Guzman below). Moreover, claim 1 does not limit the drugs to a “therapeutically effective amount”, and is thus open to an effect exerted through any other mechanisms of action.
Guzman, The Psychopharmacology of Paroxetine: Mechanism of Action, Indications, Pharmacokinetics and Dosing, March 7, 2016, available at https://psychopharmacologyinstitute.com/publication/the-psychopharmacology-of-paroxetine-mechanism-of-action-indications-pharmacokinetics-and-dosing-2204/ (“Guzman”). “Paroxetine inhibits the reuptake of serotonin by blocking the SERT transporter. The drug also can inhibit the norepinephrine transporter, but this happens at high doses. So far, no clear clinical implications for this noradrenergic feature have been described. The other property paroxetine has is its ability to block muscarinic receptors, this causes the drug to have anticholinergic effects. The importance for this in clinical practice is that central anticholinergic effects can trigger cognitive impairment in the elderly.”
Claim 10 recites the limitation “wherein the HDAC inhibitor and/or GRK2 inhibitor comprises oral administration . . .”. The claim is vague and indefinite because and inhibitor (a noun) is a compound, and a compound cannot comprise administration. In the interest of compact prosecution the Examiner interprets the claim as directed to: “The method of claim 1, wherein the administration of the HDAC inhibitor and/or GRK2 inhibitor comprises oral administration . . .”.
Claim 14 recites the limitation “wherein the infection is pneumonia or post-injury pneumonia”. The claim is vague and indefinite because “pneumonia” is a disease, not an “infection”, though its cause may be an infectious agent. The Merriam-Webster medical dictionary defines pneumonia as “an acute disease that is marked by inflammation of lung tissue accompanied by infiltration of alveoli and often bronchioles with white blood cells (as neutrophils) and fibrinous exudate, is characterized by fever, chills, cough, difficulty in breathing, fatigue, chest pain, and reduced lung expansion, and is typically caused by an infectious agent (as a bacterium, virus, or fungus).” (https://www.merriam-webster.com/dictionary/pneumonia#medicalDictionary). Infection and pneumonia are further not synonymous because “ [p]neumonia is not always caused by infection; it can also result from non-infectious factors such as environmental irritants and underlying health conditions. . . Non-infectious pneumonia causes can stem from a variety of environmental factors. Chemical exposure, allergens, and certain medical conditions may trigger this form. For instance, aspiration pneumonia occurs when food or liquid is inhaled into the lungs.” (https://healthnode.com/lung-disease/pneumonia/is-pneumonia-always-caused-by-infection)
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 2, 7, 9, 10 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2019126204 A1 to Mehra (“Mehra”), and further in view of Talsky et al., "Pharmacological interventions for traumatic brain injury", BC Medical Journal, vol. 53, no. 1, 1 February 2011, pages 26-31 (“Talsky”, of record).
Claims 1 and 2 of Mehra are directed to a method for preventing, ameliorating or alleviating neuropsychiatric symptoms and psychiatric disorders associated with traumatic brain injuries (TBI) and related disorder comprising administering to a human in need of such treatment a composition comprising opipramol in an amount effective to prevent, ameliorate or alleviate one or more symptoms of the traumatic brain injuries (TBI) related disorder, wherein the disorder is selected from the group consisting of traumatic brain injury (TBI), concussion, sport-related concussion, post-concussion syndrome, open head injury, closed head injury, contusion, etc. Claim 13 is directed to one or more additional therapeutic agents selected from the group consisting of, inter alia, paroxetine and valproic acid. In the coordinate administration methods of the invention, the opipramol and the additional therapeutic agent are administered concurrently or sequentially in any order to prevent or treat one or more symptoms of the targeted disorders including traumatic brain injury (TBI) and related disorders. ([0020]). Examples of routes of administration that may be used include injection (subcutaneous, intravenous, parenterally, intraperitoneally, intrathecal), oral, inhalation, rectal and transdermal. ([0032]).
Mehra discloses Applicant’s claimed method with Applicant’s claimed drug combination and specifically elected species, but does wherein the drugs are disclosed in a list of other active ingredients. Even so, the individual use of Applicant’s claimed drugs/ elected species, as individual classes of drugs, for use in Applicant’s claimed method, is also known in the art.
Talsky summarizes a number of pharmacological interventions used in the treatment/management of traumatic brain injury (abstract; and page 27, table). Among others, Talsky mentions the use of SSRIs (including paroxetine, fluoxetine, sertraline, citalopram) and anticonvulsants (including valproic acid), to treat symptoms in traumatic brain injury patients (page 28, column 3 and page 29, columns 2 and 3). It is noted that the SSRIs mentioned in Talsky are reported in the present application as GRK2 inhibitors, and paroxetine is the preferred HDAC inhibitor according to the present application.
Accordingly, it would have been obvious to a person of skill in the art before the effective filing date of the claimed invention to combine the teachings of Mehra and Talsky in order to practice Applicant’s claimed invention with a reasonable chance of success. The skilled artisan would have been motivated to do so since both references specifically disclose the use of the same classes of compounds, to specifically include Applicant’s claimed species, for the treatment of trauma, e.g. traumatic brain injury. The skilled artisan would have been motivated to do so since it is well known in the art that polypharmacy has the potential to achieve better therapeutic efficacy through more than one mechanism of action.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over WO 2019126204 A1 to Mehra (“Mehra”), and further in view of Talsky et al., "Pharmacological interventions for traumatic brain injury", BC Medical Journal, vol. 53, no. 1, 1 February 2011, pages 26-31 (“Talsky”, of record), as applied to claims 1, 2, 7, 9, 10 and 12 in the 35 U.S.C. 103 rejection above, and further in view of Queiroz et al., "Effects of sodium valproate on the immune response", INTERNATIONAL JOURNAL OF IMMUNOPHARMACOLOGY, vol. 14, no. 7, 1 October 1992 (“Queiroz”, of record), Chait et al., "Unravelling the antimicrobial action of antidepressants on gut commensal microbes", SCIENTIFIC REPORTS, vol. 10, no. 1, 21 October 2020, pages 1-11 (“Chait”), and Schellenberg et al., Pneumonia in Trauma Patients, Infection and Trauma (M Sartelli, Section Editor), Published: 27 July 2017, Volume 3, pages 308–314 (2017) (“Schellenberg”).
Mehra and Talsky are discussed in the 35 USC 103 rejection above.
Since Mehra and Talsky teach treating trauma with Applicant’s claimed compounds and their combination, they will also necessarily teach the sequalae and secondary diseases resulting from it, such the development of infection, to include infection results in the development of pneumonia or post-injury pneumonia, per Applicant’s claim 14. Even so, the prior art below further teaches that Applicant’s claimed compounds/ elected species, are further known in the art for the treatment of infection.
Queiroz relates to the resistance of animals treated with valproate (VAL) to bacterial infection (abstract) and belongs therefore to the same field and has the same purpose of the subject matter of the instant claims. Queiroz reports a study where the resistance of VAL-treated animals to infection was assessed by challenging with Klebsiella pneumoniae (abstract). According to D4 (page 1135, right-hand column, 4th paragraph), pretreatment for 3 weeks with VAL resulted in a significant increase in antibacterial resistance, parallel with a slower raise in bacteraemia (figures 2 and 3). Thus, at the time of the invention, the benefits of VAL in the therapy of bacterial infections were already known from Queiroz.
Chait relates to compounds having antimicrobial activity (title). Chait discloses that SSRIs have antimicrobial activity. Chait discloses that SSRIs such as sertraline, fluoxetine and paroxetine are efflux inhibitors in bacteria cell walls and are effective on Gram-positive bacteria. Chait also discloses the antifungal potential of SSRIs and that several SSRIs have been reported to have antimicrobial properties at high concentrations while having antimicrobial enhancer properties at lower concentrations (page 1, 2nd paragraph).
As can be seen from just Queiroz and Chait Applicant’s claimed compounds have an effect on a broad array of pathogens, i.e. Queiroz reports an effect of valproic acid on Klebsiella pneumoniae- i.e. Gram-negative bacteria, and Chait discloses an effect of paroxetine on Gram-positive bacteria bacteria and fungi.
Schellenberg discloses that pneumonia is a frequent complication among trauma patients, and that its development among trauma patients translates to poorer outcomes. It further discloses that nosocomial infections, including pneumonia, increase mortality and result in significantly longer hospital and ICU length of stay among trauma patients. (Abstract, Introduction).
Accordingly, it would have been obvious to a person of skill in the art before the effective filing date of the claimed invention to combine the teachings of Mehra, Talsky, Queiroz, Chait and Schellenberg in order to practice Applicant’s claimed invention with a reasonable chance of success. The skilled artisan would have been motivated to do so since both Mehra and Talsky specification teach Applicant’s elected species and classes of drugs as useful for the treatment of trauma, and Queiroz and Chait further teaches them to be directly effective further for the treatment of infection. Further motivation to do so is because Schellenberg teaches that trauma frequently leads to the complication of infection and pneumonia. Accordingly, the art as a whole teaches the use of Applicant’s claimed drugs for use in Applicant’s claimed method.
The Examiner notes that Applicant’s specification shows some synergy data on infection after trauma vis-à-vis the combination of paroxetine and valproic acid tested at a single dose each in Fig. 6B. However, Applicant’s claims are considerably broader than the synergy data shown, as they encompass a considerably greater number of compounds for which neither testing was done, nor synergy shown, and as the claims are further not limited to a synergistically effective amount.
Other relevant art
The Examiner also notes for the record the following relevant art over which no rejections were made solely in view of its cumulative nature.
-Williams et al., "Histone Deacetylase Inhibitors: A Novel Strategy in Trauma and Sepsis", SHOCK, vol. 52, no. 3, 1 September 2019, pages 300-306 (“Williams”, of record)
Williams is a review article that summarizes findings in relation to the use of HDACi, including valproic acid, in both trauma and sepsis (e.g. abstract and Table 1). Williams mentions that among numerous HDACis, valproic acid appears to be the most promising (page 304, conclusion).
-Yue et al, "Selective Serotonin Reuptake Inhibitors for Treating Neurocognitive and Neuropsychiatric Disorders Following Traumatic Brain Injury: An Evaluation of Current Evidence", Brain Sciences, vol. 7, no. 93, 25 July 2017, pages 1-26 (“Yue”, of record)
Yue is a review that summarizes findings in relation to the use of SSRIs, including paroxetine, for treating neurocognitive and neuropsychiatric disorders following traumatic brain injury (e.g. title, abstract, table 1).
Thus, Williams and Yue are evidence that at the relevant date, the use of these compounds was already known in the treatment/management of trauma patients. Combining compounds known for having useful activity in the treatment of trauma patients to achieve and alternative treatment does not require inventive skills.
-Biesterveld et al., "Valproic acid treatment rescues injured tissues after traumatic brain injury", JOURNAL OF TRAUMA AND ACUTE CARE SURGERY, vol. 89, no. 6, 1 December 2020, pages 1156-1165 (“Biesterveld”, of record)
Biesterveld discloses that valproic acid treatment rescues injured tissues after traumatic brain injury. (Title, Abstract).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SVETLANA M IVANOVA whose telephone number is (571)270-3277. The examiner can normally be reached 8:30-5:00.
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/SVETLANA M IVANOVA/ Primary Examiner, Art Unit 1627
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