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
This Application is a 371 National Stage Entry of PCT/US2022/051052, filed on November 28, 2022, and claims benefit to domestic Provisional Application No. 63/283,940 filed on November 29, 2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on November 15, 2024 is acknowledged and has been considered.
Status of the Claims
Acknowledgement is made of the claims in the filed Application 18/712,594; Claims 1-7, 10-19, 28-29 are original; claim 30 is amended and claims 8-9, 20-27 and 31 are cancelled. No new matter was added. Thus, claims 1-7, 10-19 and 28-30 represent all the claims currently under consideration.
Claim Rejections - 35 USC § 112b
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 3-6 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.
Applicant recites in parent claim 1, a method of treating traumatic brain injury with a composition comprising an inhibitor of multiple kinase families; claim 3 recites wherein the inhibitor is selected from an inhibitor of a Src family kinase, an Abl family kinase, c-kit family kinase or a combination thereof; in claim 4, wherein the inhibitor inhibits a Src-family tyrosine kinase selected from the recited Src family; claims 5 and 6 limit that further as recited. While Applicant recites an inhibitor of multiple kinase families in claim 1, the limitations in claim 3 only give the option of an inhibitor that inhibits a single family, the tyrosine kinase family; additionally the limitations in claims 4-6 are only directed towards kinase from the Src family.
Regarding claims 3-6, Examiner suggests that the Applicant considers including language to make clear the kinase inhibitor be an inhibitor of at least a Src family kinase, an Abl family kinase, c-kit family kinase or as recited, (claim 3); wherein the inhibitor inhibits at least a Src-family tyrosine kinase selected from, as recited, (claim 4); wherein the inhibitor is at least an inhibitor of Src as further recited(claim 5); wherein the inhibitor is at least an inhibitor of Src with further limitations as recited (claim 6).
Claim interpretation: For the purpose of compact prosecution, Examiner applied the above claim interpretation in view of the specification and prior art in the field.
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.
Claim 1 is rejected under 35 U.S.C. 103 as being unpatentable over Dash et al. 2011, (Dash et al., “Involvement of the glycogen synthesis kinase-3 signaling pathway in TBI pathology and neurocognitive outcome” PLoS ONE, Vol. 6, Issue 9; e24648 page 1-11; Published September 15, 2011) here on after, Dash, in view of Nair, 2016 (Nair A.B. and Jacob S.”A simple practice guide for dose conversion between animals and human”, J Basic Clin Pharma, 2016, Vol. 7, Issue 2, page 27-31; Published March-May 2016), hereon after Nair, and Kakani, Medical calculator (Kakani G., Tools to Health, mEq to milligrams (mg)- Medical Calculator, available at, toolstohealth.com/meq-to-mg-calculator; Accessed Aug 7, 2026) hereon after, Kakani, and further in view of Shim, 2016, (Shim S. and Stutzmann, G., “Inhibition of glycogen synthase kinase-3: An emerging target in the treatment of traumatic brain injury”, J. of Neurotrauma, 33, pages 2065-2076; Published on December 1, 2016), hereon after, Shim,
Regarding the instant claim 1; Dash teaches a study using lithium in traumatic brain injury (TBI) in rat models. The reference reveals traumatic brain injury (TBI) sets in motion cascade of biochemical changes that result in delayed cell death and altered neuronal architecture (abstract). Dash informs artisans that lithium, which is known for its use, as lithium therapy for bipolar patients, has been shown to attenuate multiple pathological processes that are reported to contribute to TBI pathophysiology such as apoptosis, oxidative stress and mitochondrial and endoplasmic dysfunction. For example, pre-treatment with lithium protects cultured neurons from glutamate-induced cell death and reduces oxidative stress associated with neuropeptide S; it also reduces N-acetyl aspartate (NAA) a marker of neural injury in bipolar patients and increases more gray matter (page 9).
Dash teaches that when lithium administered to mice post-TBI and continued for additional 5 days, the following was observed; a) lithium significantly improves hippocampal function as indicated by improved learning and memory in the Morris water maze task, tested days 14-25 post injury (page 9); b) further, inhibition of glycogen synthase kinase-3 (GSK-3) effectively reduces apoptosis following a number of stimuli (abstract). Dash points out that although studies have shown that cell death after TBI can continue for weeks to months, the majority of the hippocampal cell loss occurs within the first few days after the injury (page 10).
Using rodent models, Dash reveals that, following TBI, animals were injected (s.c.u - subcutaneously) with 0.5 ml (1 mEq/ kg lithium) or vehicle after 30 minutes post-injury, and once every 24 hours thereafter for the first 5 days. Dash further discloses that for biochemical analysis naïve rates were given s.c.u. injection of lithium (0.1, 0.25, 0.5 or 1 mEq/ kg) or vehicle, once a day for 5 days (page 2). From the study, Dash shows that lithium influences several neurochemical cascades, including inhibiting GSK-3, reduced hippocampal neuronal cell loss, and learning and memory improvements (page 5 and page 9).
Dash ends with a discussing on the high therapeutic dose for lithium in bipolar patients and occurrence of adverse events associated with the high doses; discloses future studies to determine lowers doses in combination therapies that could help reduce consequences of TBI while minimizing adverse events associated with high doses of the drugs (page 10).
How prior art differs from instant claim: Dash teaches treatment of TBI in mice models with doses administered mEq/ kg and does distinctly teach a human subject with a dose of less than or equal to 20 mg/day. Dash teaches lithium inhibits GSK3 kinase but does not teach inhibition of other kinases.
Regarding the dose administered; Kakani’s Medical calculator provides a step-by-step calculation for converting the milliequivalents (mEq)/kg to milligrams (mg)/kg of ions, such as lithium. Thus using the calculator, doses of 0.1 mEq/ kg to 1.0 mEq/kg of lithium, upon conversion to mg/kg, become 0.694 mg/ kg to 6.94 mg/kg of lithium.
Additionally, Nair teaches conversion of doses between species, as displayed in Table 1 in the reference (Nair, page 29). To convert mice doses to human equivalent dose (HED), Nair teaches the mice dose should be multiplied by 0.081 – based on Reference human body weight of 60 kg. Thus, per Nair’s teachings, for an example, converting 0.694 mg/kg dose of mice to a human (60 kg) dose, becomes a dose of 3.37 mg/ day - (Based on Nair, Table 1, page 29).
Regarding an inhibitor of multiple kinase families, Shim teaches the use of lithium in treatment of TBI through inhibition of glycogen kinase-3 (GSK-3), a serine/ threonine kinase. Shim discloses that, lithium, a direct and indirect GSK-inhibitor, was found to exert neuroprotective actions, promote cell survival and reduce cognitive impairment, a major symptom in TBI (Table 1, page 2070). Further, after TBI, lithium exerts its neuroprotective effects by the following; blocking GSK-3 activity and activating receptor tyrosine kinase (RTK) signaling pathway via stimulating phosphatidylinositol 3 kinase in addition to directly blocking GSK-3. Further, Shim teaches that lithium blocks protein kinase C activity by inhibiting inositol monophosphatase and activities of extracellular signal regulated protein kinase (ERK)/ mitogen-activated protein kinases (MAPK) cascade (page 2069). Shim suggests that multiple signaling pathways are needed to produce robust antiapoptotic / neuroprotective action against TBI and improve clinical outcome. Additionally, Shim teaches, lithium treatment improved CCI-induced behavioral and neurological symptoms including anxiety-like behavior and motor dis-coordination; and these molecular changes were correlated with increased GSK-3β phosphorylation (GSK-3β inhibition) ( pages 2069-2070).
Therefore it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to arrive at the instant invention with reasonable expectation of success. Prior art, Dash and Shim, teach the use of lithium to treat TBI by inhibiting GSK-3, a serine/threonine kinase; lithium also inhibits the receptor tyrosine kinase (RTK), protein kinase C and ERK /MAPK pathways – as claimed in instant claim a method of treating TBI comprising an inhibitor of multiple kinase families. Dash discloses inhibitor doses of 0.1, 0.25 and 0.5 mEq/kg, which based on Kakani calculator (mEq/kg to mg/kg conversion) and Nair’s (animal to human), HED conversions for a 60 kg human, result in a dose of less than 20 mg/day in a human. Notably, Applicant indicates in the instant disclosure that the values administered in the invention are based on weight of the subject and the values provided are based on 60 kg human – (Specification page 9 line 28).
Per MPEP § 2144.05(I), a prima facie case of obviousness exists when the claimed invention overlaps with, or is close to prior art. The instant invention, claim 1 is drawn towards a method of treating TBI in a human subject comprising of administering an inhibitor of multiple kinase families to a subject where the inhibitor is administered at a dose of less than or equal to about 20 mg/day. Prior art teaches traumatic brain injury sets in motion a cascade of biochemical changes that results in cell death and altered neuronal design; that multiple signaling pathways are needed to produce robust antiapoptotic / neuroprotective action against TBI and improve clinical outcome; that lithium as an inhibitor of several kinases and signaling pathways related to TBI; prior also teaches lithium is used to treat TBI in mice models; mice models are known to be relevant to human treatment; in addition lithium is a known drug used to treat humans with bipolar disorders; prior art further teaches the importance of lower therapeutic doses to reduce consequences of TBI while minimizing adverse events associated with high doses of the drugs.
Accordingly, one of ordinary skill would be motivated to arrive at the instant invention because of at least any of the following reasons (i) it is known from prior art that TBI affects biochemical changes that can be inhibited through multiple kinases or kinase families (ii) the kinase inhibitors are known from prior art to affect other downstream or upstream pathways (iii) there are mice models that have shown improved TBI outcomes when treated with an inhibitor of multiple kinase (iv) lower doses in TBI treatment would reduce consequences of TBI while minimizing adverse events associated with the drugs.
Claims 1-7, 10-19, 28 and 30 are rejected under 35 U.S.C. 103 as being unpatentable over Yu et al. 2016, (Yu et al., “Oxidation of KCNB1 Potassium Channels Causes Neurotoxicity and Cognitive Impairment in a Mouse Model of Traumatic Brain Injury”, Journal of Neuroscience, 36(43), pg. 11084-11096, Published on October 26, 2016), hereon after Yu, in view of Liu, 2017 (Liu DZ., “Repurposing cancer drugs to treat neurological diseases – Src Inhibitors as examples”, Neural Regen. Res., Vol. 12, Issue 6. Pages 910-911; Published June 2017), hereon after, Liu and Martens U. M., 2018, (Uwe M. Martens, (Editor); Dasatinib by Lindauer and Andreas Hochhaus, pages 29-68, in “Small Molecules in Hematology”, Third Edition, Series: Recent Results in Cancer Research, Vol. 212; Springer International Publishing AG, 2018. ISBN 978-3-319-91439-8 (eBook); Published on August 1, 2018), hereon after, Martens.
Yu teachings on traumatic brain injury using mice models that mimic human TBI found that dasatinib, a Src tyrosine kinase inhibitor, ameliorates inflammation, neurodegeneration and neuronal death and improves behavioral deficiency following the lateral fluid percussion (LFP) injury.
Yu’s study demonstrates that traumatic brain injury induces oxidation of KCNB1 potassium channels which activates Src-tyrosine kinase-dependent signaling and promotes neuronal injury and cognitive impairment. Yu informs artisans that, KCNB1 protein aggregates favor the activation of Src tyrosine kinases and downstream Jun N-terminal kinases (JNK) that lead to apoptosis and release of more reactive oxygen species (ROS) by presumably destabilizing the mitochondria (page 11084-85). The reference shows that genetic suppression of KCNB1 oxidation is protective in TBI (11085).
Yu’s reference used transgenic mice harboring human KCNB1 wild-type (Tg-WT) or a nonoxidable C73A mutant (Tg-C73A) in cortex and hippocampus to determine whether oxidized KCNB1 channels affect brain function. Animals were subjected to moderate traumatic brain injury condition characterized by extensive oxidative stress (abstract). Yu teaches this was done using the lateral fluid percussion (LFP) method which produces defects that reflect outcomes observed in human victims of TBI (page 11085).
Regarding instant claims 1 and 3-7, Yu’s teachings disclose a study that proved an inhibitor of Src kinase family ameliorates the effects of traumatic brain injury (instant claims 1, 3-6). The reference discloses that transgenic mice were encoded with human KCNB1 tagged to the human influenza hemagglutinin (HA) tag in the C terminus inserted in the mouse to obtain Tg-WT and Tg-C73A mice. Yu teaches that dasatinib, a Food and Drug Administration approved inhibitor of Src tyrosine kinase was used to impinge on the proapoptotic signaling pathway activated by oxidized KCNB1 channels; thus, typical lesions of brain injury, namely inflammation (astrocytosis), neurodegeneration and cell death, were markedly reduced in Tg-C73A and dasatinib-treated non-Tg animals (instant claim 3-7).
Accordingly, Tg-C73A mice and non-Tg mice treated with dasatinib exhibited improved behavioral outcomes in motor (rotarod) and cognitive (Morris water maze) assays compared to controls. Moreover, the activity of Src kinases, along with oxidative stress, were significantly diminished in Tg-C73A brains (abstract). Notably, Yu informs artisans that the study sought to determine whether pharmacological strategies that act to inhibit the activities of Src-kinases could improve neuronal lesions and behavioral outcome of LFP-injured animals and used dasatinib an FDA approved Src kinase inhibitor that is blood-brain barrier permeable and pharmacologically active in the brain (page 11092).
Regarding instant claims 11, 12, 13, 14, and 30, Yu teaches dasatinib was administered to the animals intraperitoneally at 25 mg/ kg. Each mouse was subjected to a daily dose of either vehicle or dasatinib solution via an intraperitoneal injection starting from the day of surgery, 2 hours after injury – as in instant claims 11-14 and 30. (page 11086).
Regarding instant claims 13, 17 and 18, Yu teaches that to expose the channels to controlled and reproducible conditions of oxidative stress, the animals were subjected to mild to moderate traumatic brain injury - which is associated with extensive oxidation during the secondary injury -using the lateral fluid percussion (LFP) method (instant claim 17). Yu further explains that LFP produces both focal and diffuse brain injury and is associated with extensive axonal damage and cell death that result in long-term neuromotor and cognitive deficits (page 11085). Additionally, Yu teaches that at this moderate level of injury ~10% of animals died as a result of the injury within the acute posttraumatic period (15 min), generally from respiratory failure and pulmonary edema, which is a normal and anticipated feature of the TBI model because it mimics human TBI - as in instant claims 13 and 18 (page 11086).
Regarding instant claims 28; Yu teaches that dasatinib is FDA approved drug sold under the commercial name SPRYCEL® and currently used to treat certain forms of leukemia, and further from their study, dasatinib ameliorates inflammation, neurodegeneration and neuronal death and improves behavioral deficiency following the LFP injury (page 11085). One of ordinary skill in the art would understand that conventional formulations of prescription drugs comprise pharmaceutically acceptable carriers or excipients.
Prior art defers from instant claims as follows: Yu’s teachings disclose that dasatinib, an inhibitor of Src kinase family ameliorates the outcome of traumatic brain injury in transgenic mice and that dasatinib was administered to at 25 mg/kg of daily; Yu does not distinctly teach the following (a) an inhibitor administered at a dose equal to about 20 mg/day or less as in recited in instant claims 1, 10, 15, 16 and 19; (b) wherein the inhibitor has an in vitro IC50 of less than about 4nM in cell-free assays as recited in instant claim 2; (c) an inhibitor that inhibits Src family with the limitations recited in claims 3-6.
Liu 2017, is a reference discussing repurposing cancer drugs to treat neurological diseases using Src inhibitor as examples. Liu discusses aberrant cell cycle diseases – and states aberrant cell cycle is one of the hallmarks of many tumors in cancers and also observed in postmortem and /or animal studies of dying neurons in a series of neurological diseases such as Alzheimer’s (AD), Parkinson’s (PD), traumatic brain injury (TBI), intracerebral hemorrhage (ICH), epilepsy, among others (Aberrant cell cycle diseases – page 910).
Liu informs artisans that although most cancers have multivariate causes, the various causes seem to result in a common outcome – cell cycle re-entry, mediated by mitogenic pathways such as Src/Ras/ Raf/MEK1, 2/ERK1,2 (illustrated in Figure 1 - Liu). The references states that apart from the core cell cycle molecules - cyclins and cyclin-dependent kinases (CDKs), strategies of interfering with these mitogenic molecules and signaling pathways have been tested to treat cancer; that a significant advantage of drug repurposed drugs is that they have already passed a significant number of toxicity and other tests in humans, detailed information is available on their safety and the risk of failure for reasons of adverse toxicology is reduced. (Cancer drugs that inhibit cell cycle – page 910).
Liu teaching on Src in cancer therapy discloses the following; that due to aberrant activation of Src up-stream activations or mutations in Src or C-terminal Src (Csk), Src can be activated; that there are several Src inhibitors including dasatinib, in clinical trials for various cancers; the reference points out two Src inhibitors, among them dasatinib, that have been approved as prescription drugs to treat individuals who have Philadelphia chromosome-positive chronic myelogenous leukemia but no longer benefit from or did not tolerate other treatments (Src in cancer therapy – page 910).
Liu goes on to inform artisans that, in relation to neurological disease, a large number of studies have revealed that the molecules released following acute brain injury can activate Src and over activated Src causes neurons to enter the aberrant cell cycle and results in post-mitotic death. Liu reveals that some Src inhibitors, PP2 and AZD0530, have been tested in treatment of TBI among other neurological disorders. Liu concludes by informing artisans that cancer and neurological disorders share common molecular pathology of cell cycle re-entry and cancer drugs that can block aberrant cell cycle to kill tumor cells in treatment of cancers, can be repurposed to protect mature neurons from death in treatment of neurological disorders such as TBI (page 911).
Regarding claims 3-7; Liu teaches dasatinib is Src inhibitor (instant claim 7); that Src is a family of non-receptor tyrosine kinases that include at least nine family members: c-Src (the cellular counterpart of oncogene v-Src), Fyn, Hck, Lck, Lyn, Blk, Fgr, Yes and Yrk (instant claim 3-5). Liu reveals that the expression of Src family members is tissue and cell type specific; that although c-Src, Fyn, Yes and Yrk are expressed ubiquitously in all cell types, others such as, Hck, Lck, Lyn, Blk and Fgr are generally found in brain and hematopoietic cells (instant claim 6); further that brain and platelets express 5-200 fold higher levels of Src kinases than most other cells; and that different Src kinases are often found to compensate for one another such as c-Src and Fyn ( Src, Src family members – page 910).
Martens 2018, teachings on dasatinib reveal the following; dasatinib is an orally available short-acting inhibitor of multiple tyrosine kinases (page 30); that dasatinib, is a second-generation small molecule tyrosine kinase inhibitor (TKI), after imatinib (first-generation), and is a BCR-ABL inhibitor that inhibits BCR-ABL with greater potency compared to other BCR-ABL inhibitors (page 32). Martens further teaches that dasatinib binds to the ATP-binding pocket of BCR-ABL in both the active and inactive conformations and has been found to be 325-fold more potent than imatinib for inhibiting unmutated BCR-ABL – with an inhibitor IC50 of 0.6 nm/L for dasatinib compared to 280 nmol/L for imatinib (page 34).
Thus, dasatinib is an effective treatment for the BCR-ABL-driven diseases including gastrointestinal stromal tumors, chronic myeloid leukemia (CML), acute myelogenous leukemia (AML), Philadelphia-chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), similar to imatinib. As such, dasatinib is approved for treatment of CML (all phases), including children and for the treatment of Ph+ ALL, resistant or intolerant to prior imatinib treatment (page 33).
Regarding inhibition of multiple kinase families as recited in instant claim 1,3-7; Martens teaches that in addition inhibiting BCR-ABL, dasatinib is a potent inhibitor of the SRC family of kinases (Src, Lck, Hck, Yes, Fyn, Fgr, Blk Lyn, Frk), receptor tyrosine kinases (c-Kit, PDGFR, DDR1 and 2, c-FMS, ephrin receptors) and TEC family kinases (TEC and BTK) (Introduction page 31-33).
Regarding an inhibitor that has an in vitro IC50 of less than about 4 nM in cell-free assays as in instant claim 2, Martens shows inhibitory activity of dasatinib on selected tyrosine kinases with several of them below 4 nM (Table 1, page 33) and as shown, dasatinib inhibits Src with IC50 of 0.5 nm/L (page 35).
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Regarding the dose of less than or equal to 20 mg/day as recited in instant claims 1, 10, 15-16, and 19; While, Martens teaching on dasatinib is not directed to traumatic brain injury; the reference teaches that for treatment of CML, ALL Phases and Ph+ ALL, dasatinib has been administered to patients in doses ranging from 15 mg/day to 240 mg/day once or twice daily (Section 4.3.3 - page 39).
Regarding oral administration as recited in instant claim 18; Martens teachings reveal dasatinib is administered orally and from the pharmacokinetic profile it is rapidly absorbed. (section 4.1 page 38).
Therefore, it would have been obvious before the effective filing date of the instant application to combine the teaching of Yu in view of Liu and Martens to arrive at the instant claimed invention with reasonable expectation of success. Yu teaches Src activation is directly in involved in TBI injury signaling; discloses the effects on KCNB1 oxidation following brain injury and that blocking Src associated pathways with dasatinib, an FDA approved cancer drug, improves TBI related outcomes.
Liu teaches cancer and neurological disorders, such as TBI, share a common molecular pathology of cell cycle re-entry; that Src activity has been shown in both kinds of conditions, that Src kinases are tissue and cell type specific; and some Src kinases occur at higher levels in the brain; further that some Src inhibitors have been tested in treatment of TBI. Martens teachings disclose dasatinib is a potent multikinase inhibitor, including an inhibitor of Src kinase; that dasatinib inhibits BCR-ABL with greater potency compared to other inhibitors and has 325-fold more potency compared to first generation TKI inhibitor imatinib; thus it is administered at much lower doses.
Per MPEP § 2143 (I)(A) and (D), a prima facie case of obviousness exists for combining prior art elements according to known methods to yield predictable results; additionally, a prima facie case of obviousness exists for applying a known technique to a known method or product ready for improvement to yield predictable results.
Accordingly, It would have been obvious to apply Yu’s teaching combined with Liu’s and Martens to arrive at the instant claimed invention. Yu teaches on, an inhibitor of multiple kinase families used in treatment of TBI in mice models that mimic human TBI at low doses (instant claim 1), Yu uses dasatinib, FDA approved Src inhibitor (instant claims 3-7), Yu teaches administration of daily doses (instant claims 11-12), where the inhibitor was administered between 0.1 and 9 hours following TBI (instant claim 14). Yu teaches treatment of TBI in mice models mimic acute, mild to moderate traumatic brain injury in humans (instant claim 13 and 17); Yu discloses intraperitoneal administration (instant claim 30) and that dasatinib is already a known FDA approved drug for treatment of leukemia but also ameliorates inflammation, neurodegeneration and neuronal death and improves behavioral deficiency following TBI.
Both Liu and Yu disclose dasatinib as an approved prescription drug, thus one of ordinary skill in the art would understand formulations comprise of pharmaceutically acceptable carrier or excipient (instant claim 28). Liu teaches cancer and TBI share some common molecular pathology and that cancer drugs that block aberrant cell cycle to kill tumor cells in cancer treatment can be used to protect mature neurons from death in treatment of neurological diseases that include TBI. Liu teaches Src kinase family is a target for treatment in both cancers and neurological diseases. Liu teaches some Src inhibitors have been tested in treatment of TBI. Martens teaches dasatinib, an FDA-approved Src inhibitor is also an inhibitor of multiple kinase families (instant claims 1 and 3-7), with 325-fold more potency for the ABL proteins as well as other kinases, than the first generation imatinib and is thus administered at lower doses; doses of less or equal to 20 mg/day (as in instant claim 1, 10, 15-16 and 19), with an in vitro IC50 of less than 4 nM (as in instant claim 2).
Therefore one of ordinary skill in the art would be motivated to arrive at the instant claimed invention because of at least any of the following reasons; (i) dasatinib is a potent Src inhibitor, and an inhibitor or multiple kinases and has been shown to improve outcome in TBI; (ii) a large number of studies have revealed molecules released following acute TBI activate Src (iii) some Src inhibitors have been tested for treatment of TBI as also evidenced by Yu (iv) dasatinib is a much more potent Src inhibitor (v) the pharmacological profile of dasatinib as an FDA-approved cancer drug is already known and (vi) dasatinib can be administered at much lower doses that have similar efficacy with reduced toxicity or side effects.
Claims 1-7, 10-19, 28-29 and 30 are rejected under 35 U.S.C. 103 as being unpatentable over Yu et al. 2016, in view of Liu, 2017 and Martens U. M., 2018 and further in view of Bristol-Myers Squibb, 2013, (Bristol-Myers Squibb, Clinical Protocol CA180372, A Phase 2 Multi-Center, Historically-Controlled Study of Dasatinib Added to Standard Chemotherapy in Pediatric Patients with Newly Diagnosed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia; Revised Protocol: 05 Trial dates, 01-June-2011 to 28-Oct-2013), hereon after Bristol-Myers.
Regarding claims 1-7, 10-19, 28 and 30, all the teachings Yu, Liu and Martens as discussed in the above 35 U.S.C. 103 rejection are incorporated herein.
Regarding instant claims 29; Bristol-Myers 2013’s clinical trial protocol although not directed to TBI, discloses dasatinib is formulated as a tablet (as in instant claim 29). Furthermore, the protocol discloses dasatinib tablets of different potency ranging from 5 mg tablets, 20 mg tablets, 50 mg tablets as well as a potency of 10 mg/ ml for the powder form of dasatinib in oral suspension (page 36-37).
Further regarding claims 1, 10, and 15-16 which recite doses of between 10 and 20 mg, Bristol Meyer’s discloses dasatinib is available in tablets of 5 mg, 20 mg and 50 mg.
Liu teaches Src inhibitors used as cancer drugs can be repurposed to treat TBI; Further, Liu’s teachings reveal molecules released following TBI activate Src and Src inhibitors as important targets in the treatment of TBI; but Liu also reveals that Src kinases play an important roles in proliferation of neuronal progenitor cells that exist throughout the mammalian brain and serve as a source of newborn brain cells in neurogenesis; therefore Src inhibitors that prevent tumor growth and neuronal growth may impair neurogenesis and lead to cognitive side effects. Liu concluding suggestions reveal considerations when treating neurological disorders which include the effective benefit to patients without causing severe cognitive and other side effects. Therefore, based on known prior art it would have been obvious to one of ordinary skill in the art to have an inhibitor administered at lower doses (as in instant claim 1); wherein the inhibitor is administered at a dose of less or equal to about 20 mg/ day; or wherein the dose comprises about 10 mg/day to about 20 mg/day (as instant claim 10,15 and 16).
Accordingly, it would have been obvious before the effective filing date of the claimed invention to arrive at the instant claimed invention - a method of treatment of TBI with an inhibitor of multiple kinase families wherein the composition is administered to the subject as a tablet or pill and wherein the inhibitor is administered at a dose of less than or equal to about 20 mg/kg; or wherein the dose is about 10 mg/day to about 20 mg/day - with reasonable expectation of success.
Per MPEP § 2144.07, a prima facie case of obviousness exists for the selection of known material based on its suitability for its intended use. Bristol Myers has disclosed 5 mg and 20 mg dose strength tablets for dasatinib, a potent Src inhibitor.
Liu teaches Src inhibitors used as cancer drugs can be repurposed to treat TBI and can be useful to benefit TBI patients.
One of ordinary skill in the art would have been motivated to arrive the instant claimed invention because of at least any of the following reasons (i) dasatinib is prescription drug formulated as tablet or pill; (ii) dasatinib is available as tablets of 5 mg, 20 mg and as 10 mg/ ml for the powder form of dasatinib in oral suspension (iii) dasatinib is a potent Src inhibitor whose safety profile is already known.
Conclusion
No claims are found allowable.
Claims 1-7, 10-19, and 28-30 are rejected.
Other Related Prior Art Not used in the Office Action:
Su et al. 2015, (Su et al. “Imatinib treatment reduces brain injury in a murine model of traumatic brain injury” Frontiers in Cellular Neuroscience, Vol. 9, Article 385, pgs. 1-12; Published on 07 October 2015)
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/P.O./Examiner, Art Unit 1627
/Kortney L. Klinkel/Supervisory Patent Examiner, Art Unit 1627
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