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 CIP of 16/742,131 filed 01/14/2020 now Patent number 11357823.
Claim Status
Claims 1-8, 14-26 are pending. Claims 1, 16 and 25 are amended. Claims 9-13 are canceled. Claims 1-8, 14-26 are being examined on the merits in this office action.
Claim Objections - Withdrawn
The objection to claim 1 is withdrawn in view the claim amendments.
Claim Rejections - Withdrawn
The rejection of claims 1-8, 14-24 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, is withdrawn in view of the claim amendments.
The rejection of claims 1, and 9-13 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in view of the claim 1 amendments and cancelation of claims 9-13.
Response to Amendment
The Declaration under 37 CFR 1.132 filed 05/13/2026 is insufficient to overcome the rejection of claims 1-26 based upon35 U.S.C. 103 as set forth in the last Office action because the cited references render obvious the claimed invention.
Arguments made in the Declaration are such that Annexin A5 (SY-005) produces significant improvements in neurological function (mNSS scores), near-complete restoration of behavioral function (beam balance testes), complete elimination of cerebral infarct area, reduces neuronal apoptosis (TUNEL staining) and promotion of neuroregeneration (MCM2 and DCX double staining) (Page 2-14 of Declaration).
The arguments presented above have been fully considered but are unpersuasive. Cited references teach that Annexin A5 reduces proinflammatory cytokines. Feng teaches that the Annexin A5 treatment described therein inhibits the proinflammatory effect of TNF in disorders including trauma [0042] and that annexin A5 inhibits TNF-α and IL-1β and IL-6 [0034, 0043]. Feng teaches that inflammatory disorders are often induced by pro-inflammatory cytokines, such as tumor necrosis factor (TNF; also known as TNFα or cachectin), interleukin (IL)-Ia, IL-I β, IL-6, IL-8, IL-18, interferonγ, platelet-activating factor (PAF), macrophage migration inhibitory factor (MIF), and other compounds [0006, 0040, 0043]. It is known in the art that TBI is followed by a robust inflammatory response of inflammatory cytokines such as IL-1, IL-6, TNF and TGF (Abstract) and teaches treating TBI by reducing proinflammatory cytokines. Additionally, Llyod teaches that TBI causes increases production of proinflammatory cytokines causing neuronal damage and cognitive impairment (Abstract). Llyod teaches that attenuation of proinflammatory cytokines reduced neurological injury and neurobehavioral deficits (Abstract). Examiner notes that it is known in the art to treat TBI by reducing proinflammatory cytokines and it is known in the art that annexin A5 is known to reduce proinflammatory cytokines. Additionally, the instant claims recite that the treatment reduces biomarkers such as proinflammatory cytokines.
Regarding Applicant arguments of significant improvements in neurological function (mNSS scores), near-complete restoration of behavioral function (beam balance tests), complete elimination of cerebral infarct area, reduces neuronal apoptosis (TUNEL staining) and promotion of neuroregeneration (MCM2 and DCX double staining), Examiner notes that Llyod already teaches that attenuation of proinflammatory cytokines reduced neurological injury and neurobehavioral deficits (Abstract). Additionally, it is known in the art that reduction of proinflammatory cytokines shows significant improvements in neurological function (mNSS scores), near-complete restoration of behavioral function (beam balance testes), reduces neuronal apoptosis (See Chen et al. Br. J. Pharmacol. 2008; 155(8): 1279–1296). Thus, the arguments are merely the expected results of the reduction of the proinflammatory cytokines which is known to be achieved by the administration of Annexin A5. The fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). The arguments are unpersuasive.
Claim Rejections - New
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 17-24 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.
Claim 16 recites the limitation "…wherein the step of identifying…" in claim 16 line 1-2. There is insufficient antecedent basis for this limitation in the claim because claim 16 depends on claim 1 and claim 1 does not recite “identifying a subject”. Claims 17, and 21 have a similar issue. Claims 18-20, and 22-24 depend on the rejected claims and are thus rejected.
Claim Rejections - 35 USC § 103 - Maintained
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.
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 1-8, and 14-26 are rejected under 35 U.S.C. 103 as being unpatentable over Feng et al. (US20120014920A1 – hereinafter “Feng”) in view of Corrigan et al. (Journal of Neuroinflammation (2016) 13:264), Woodcock et al. (Front Neurol. 2013 Mar 4;4:18), Lloyd et al. (J Neuroinflammation. 2008 Jun 30; 5: 28) and Donkin et al. (J Neurotrauma. 2011 Feb; 28 (2): 217-24)
Feng teaches a composition that comprises annexin A5 for use in treatment of an inflammatory disorder and for use in improving organ function (Abstract), that the annexin can be useful for treatment of organ injury such as brain [0048, 0089]. Feng teaches that the Annexin A5 treatment described therein inhibits the proinflammatory effect of TNF in disorders including trauma [0042] and that annexin A5 inhibits TNF-α and IL-1β and IL-6 [0034, 0043]. Feng teaches that inflammatory disorders are often induced by pro-inflammatory cytokines, such as tumor necrosis factor (TNF; also known as TNFα or cachectin), interleukin (IL)-Ia, IL-I β, IL-6, IL-8, IL-18, interferonγ, platelet-activating factor (PAF), macrophage migration inhibitory factor (MIF), and other compounds [0006, 0040, 0043]. Feng teaches that the annexin A5 was administered at a dose including 0.2 mg/kg [0113].
Feng does not explicitly teach that the annexin A5 treated traumatic brain injury.
Corrigan teaches that traumatic brain injury (TBI) results from the head impacting with an object or from acceleration/deceleration forces that produce vigorous movement of the brain within the skull or varying combinations of these mechanical forces producing skull fractures, extradural hemorrhages, and contusions (Page 2, left col. 2nd paragraph, line 1-18). Corrigan teaches that TBI leads to the release of a variety of pro-inflammatory factors including cytokines IL-1β, IL-6, TNFα, IL-10, IL-8 (Page 2, right col., 1st and 2nd paragraph, line 1-18).
Further, Woodcock teaches that TBI is followed by a robust inflammatory response of inflammatory cytokines such as IL-1, IL-6, TNF and TGF (Abstract). Woodcock teaches that some of the biomarkers of TBI include S100B, neuron-specific enolase (NSE), and myelin basic protein (MBP) and that they have successfully been correlated with initial brain injury severity (GCS), size of brain damage (on CT/MRI scans), and neurological outcome (Glasgow Outcome Scale/Extended; GOSE). Woodcock teaches that the aim of treatment is reduced concentration of biomarkers in TBI patients (page 2, right col., 1st paragraph, line 1-16). Woodcock teaches that other biomarkers include inflammatory cytokines and can provide extent of tissue damage and are measured in brain tissue, CSF blood, serum, plasma and that treatment involves use of anti-inflammatory drugs and those that reduce the levels of inflammatory cytokines (Page 12, left col. Lines 1-20).
Further Llyod teaches that TBI causes increases production of proinflammatory cytokines causing neuronal damage and cognitive impairment (Abstract). Llyod teaches that attenuation of proinflammatory cytokines reduced neurological injury and neurobehavioural deficits (Abstract).
Regarding administering 12 hours after injury, Donkin teaches administering a compound 12 hours after TBI was able to significantly reduce edema formation, cell death, and neurological deficits (Introduction section on Page 218, left col.). Donkin teaches that the compound significantly improved motor outcome, even when administration was delayed by as much as 12 h (Abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Feng, Corrigan and Woodcock and treat traumatic brain injury by inhibiting inflammatory cytokines such as IL-1β, IL-6, TNFα, IL-10, IL-8 using annexin A5 since both Corrigan and Woodcock teach that TBI leads to release of a variety of pro-inflammatory factors including cytokines IL-1β, IL-6, TNFα, IL-10, IL-8 and treatment involves reducing the levels of the inflammatory cytokines, and Feng teaches that Annexin A5 inhibits the proinflammatory effect of TNF in disorders including trauma [0042] and that annexin A5 inhibits TNF-α and IL-1β [0034]. It would have been obvious to administer annexin A5 12 hours after the injury since Donkin teaches administering a compound 12 hours after TBI was able to significantly reduce edema formation, cell death, and neurological deficits (Introduction section on Page 218, left col.). One of ordinary skill in the art would be motivated and would have had a reasonable expectation of success in using annexin A5 in inhibiting inflammatory cytokines thus treating TBI since Feng teaches that Annexin A5 inhibits the proinflammatory effect of TNF in disorders including trauma [0042] and that annexin A5 inhibits TNF-α and IL-1β [0034]. Examiner notes that treating TBI involves reducing proinflammatory cytokines and annexin A5 is known to reduce proinflammatory cytokines in organs such as the brain and it is known reduction of proinflammatory cytokines in subjects of TBI attenuates neurological deficits and further it is known to administer compounds for treating TBI 12 hours after TBI and annexin A5 is known to be administered at dosages including the instant 0.2 mg/kg. Additionally, the recitation of attenuating neurological deficits by 38% and decreasing IL-1β by about 100% is an intended result that would naturally flow from practicing the method step of administering Annexin A5 to the instant patient population. The disclosures render obvious claims 1 and 25.
Regarding claim 2, Feng teaches the sequence of Annexin A5 (See Page 13, Table 1 on [0150]. which is 100% identical to the instant SEQ ID NO: 1.
Regarding claims 3-4, Corrigan teaches increased levels of IL-6, TNFα, IL-10, C-C motif chemokine ligand 2 (CCL2), and IL-8 peak within the first 2 days following moderate-severe TBI (Page 2, right col., 2nd paragraph, line 1-12). Corrigan teaches that traumatic brain injury (TBI) results from the head impacting with an object or from acceleration/deceleration forces that produce vigorous movement of the brain within the skull or varying combinations of these mechanical forces producing skull fractures, extradural hemorrhages, and contusions (Page 2, left col. 2nd paragraph, line 1-18). It would have been obvious to one of ordinary skill in the art to treat the type of TBI taught by Corrigan using annexin A5 since Corrigan teaches the types of TBI increased levels of pro-inflammatory cytokines and treatment involved reducing the levels of the pro-inflammatory cytokines.
Regarding claim 5, Feng teaches that the Annexin A5 is administered to subjects including humans [0038].
Regarding claim 6-8, Feng teaches that Annexin A5 anti-apoptotic properties [0075]. Feng further teaches that the Annexin A5 treatment described herein inhibits the proinflammatory effect of TNF in disorders including trauma [0042] and that annexin A5 inhibits TNF-α and IL-1β [0034] which is a symptom of TBI and that one of the symptom of the disorder is organ ischemia [0046, 0066].
Regarding claims 14-15, Feng teaches that Annexin A5 polypeptide may be used either singly or in combination with other polypeptides, anti-inflammatory or otherwise, in the preparation of a composition that treats an inflammatory disorder or treats organ dysfunction in an inflammatory disorder [0092, 0111].
Regarding claims 16-19, Woodcock teaches that several observational clinical TBI studies where S100B has been successfully correlated with initial brain injury severity (GCS), size of brain damage (on CT/MRI scans), and neurological outcome (Glasgow Outcome Scale/Extended; GOSE) (Page 2, right col., line 1-6-9). Woodcock teaches that the levels of biomarkers detected in the injured brain compared to control (Page 9, right col. Line 1-5). It would have been obvious to one of ordinary skill in the art to modify Feng and identify subjects of TBI using the methods taught by Woodstock to obtain the results or scores as instantly recited since Woodcock teaches that the tests have successfully been correlated with initial brain injury severity and provide extent of tissue damage.
Regarding claims 20-21, Woodcock teaches that the levels of biomarkers detected in the injured brain compared to control (Page 9, right col. Line 1-5). It would have been obvious to one of ordinary skill in the art to modify Feng and identify subjects of TBI using the methods taught by Woodstock to obtain the results and compare them to subjects without TBI to provide extent of tissue damage.
Regarding claims 22, Woodcock teaches that TBI is followed by a robust inflammatory response of inflammatory cytokines such as IL-1, IL-6, TNF and TGF (Abstract). Woodcock teaches that some of the biomarkers of TBI include S100B, neuron-specific enolase (NSE), and myelin basic protein (MBP) and that they have successfully been correlated with initial brain injury severity (page 2, right col., 1st paragraph, line 1-16). It would have been obvious to modify Feng and identify subjects of TBI using the biomarkers taught by Woodcock since Woodstock teaches that TBI is followed by a robust inflammatory response of inflammatory cytokines such as IL-1, IL-6, TNF and TGF.
Regarding claim 23, Corrigan teaches that traumatic brain injury (TBI) results from the head impacting with an object or from acceleration/deceleration forces that produce vigorous movement of the brain within the skull or varying combinations of these mechanical forces producing skull fractures, extradural hemorrhages, and contusions (Page 2, left col. 2nd paragraph, line 1-18). It would have been obvious to modify Feng and identify subjects of TBI that have sustained the injuries as taught by Corrigan since Corrigan teaches TBI caused by the taught methods increased levels of pro-inflammatory cytokines and treatment involved reducing the levels of the pro-inflammatory cytokines.
Regarding claim 24, Woodcock teaches that other biomarkers include inflammatory cytokines and can provide extent of tissue damage and are measured in brain tissue, CSF blood, serum, plasma and that treatment involves use of anti-inflammatory drugs and those that reduce the levels of inflammatory cytokines (Page 12, left col. Lines 1-20). It would have been obvious to modify Feng and identify subjects of TBI that have sustained the injuries using biomarkers measured in the samples as taught by Woodcock since Woodcock teaches that some biomarkers such as TNF are increased in CSF, serum and plasma following TBI (Table 1).
Regarding claim 26, Feng teaches that treatment with Annexin A5 significantly decreases TNF-α and IL-β (See Fig. 6) which is estimated to be about 50% decrease (Fig. 6D and [0032]).
Response to Arguments
Applicant's arguments filed 05/13/2026 have been fully considered but they are not persuasive.
Applicant arguments
Applicant argues that Feng does not teach or suggest treating TBI (Page 8 of arguments). Applicant argues that Corrigan does not teach using Annexin A5 to treat TBI and that the reference teaches away because it teaches narrow therapeutic windows and teaches within hours following injury (Page 8-9 of arguments). Applicant argues that Donkin does not teach the use of Annexin A5 and argues that Donkin teaches that delayed efficacy in TBI is the exception not the rule (Page 10 of arguments). Applicant argues that there is no reasonable expectation of success and further argues that the details presented in the declaration (Page 11-16 of Arguments).
Examiner’s Response
The arguments presented above have been fully considered but are unpersuasive. Examiner notes that the cited references teach that Annexin A5 reduces proinflammatory cytokines. Feng teaches that the Annexin A5 treatment described therein inhibits the proinflammatory effect of TNF in disorders including trauma [0042] and that annexin A5 inhibits TNF-α and IL-1β and IL-6 [0034, 0043]. Feng teaches that inflammatory disorders are often induced by pro-inflammatory cytokines, such as tumor necrosis factor (TNF; also known as TNFα or cachectin), interleukin (IL)-Ia, IL-I β, IL-6, IL-8, IL-18, interferonγ, platelet-activating factor (PAF), macrophage migration inhibitory factor (MIF), and other compounds [0006, 0040, 0043]. It is known in the art that TBI is followed by a robust inflammatory response of inflammatory cytokines such as IL-1, IL-6, TNF and TGF (Abstract) and teaches treating TBI by reducing proinflammatory cytokines. Additionally, Llyod teaches that TBI causes increases production of proinflammatory cytokines causing neuronal damage and cognitive impairment (Abstract). Llyod teaches that attenuation of proinflammatory cytokines reduced neurological injury and neurobehavioral deficits (Abstract). Examiner notes that it is known in the art to treat TBI by reducing proinflammatory cytokines and it is known in the art that annexin A5 is known to reduce proinflammatory cytokines. Additionally, the instant claims recite that the treatment reduces biomarkers such as proinflammatory cytokines. Examiner disagrees that Corrigan teaches away since the reference was used to teach the causes of TBI such as head impacting with an object or from acceleration/deceleration forces that produce vigorous movement of the brain within the skull or varying combinations of these mechanical forces producing skull fractures, extradural hemorrhages, and contusions. Examiner notes that it appears that Applicant is arguing the references individually. Examiner notes that one single references does not teach all the claimed limitations because the rejection is based on the combined teachings of the Feng, Corrigam, Woodcock, Lloyd and Donkin. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). The mechanism of action that is used in the instant invention to treat TBI is by the reduction of proinflammatory cytokines such as those recited in claim 22 by use of Annexin A5. Feng teaches the use of Annexin A5 to treat organ injury including the brain and teaches that Annexin A5 reduces or inhibits proinflammatory cytokines such as TNF-α and IL-1β and IL-6 [0034, 0043]. The secondary references teach that TBI is associated with an increase of proinflammatory cytokines and that treatment of TBI involves reduction of proinflammatory cytokines. The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). Examiner notes that when the teachings of the cited references are combined, the instant invention is obvious.
Regarding Applicant arguments made in the Declaration of significant improvements in neurological function (mNSS scores), near-complete restoration of behavioral function (beam balance tests), complete elimination of cerebral infarct area, reduces neuronal apoptosis (TUNEL staining) and promotion of neuroregeneration (MCM2 and DCX double staining), Examiner notes that Llyod already teaches that attenuation of proinflammatory cytokines reduced neurological injury and neurobehavioral deficits (Abstract). Additionally, it is known in the art that reduction of proinflammatory cytokines shows significant improvements in neurological function (mNSS scores), near-complete restoration of behavioral function (beam balance testes), reduces neuronal apoptosis (See Chen et al. Br. J. Pharmacol. 2008; 155(8): 1279–1296). Thus, the arguments are merely the expected results of the reduction of the proinflammatory cytokines which is known to be achieved by the administration of Annexin A5. The fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). The arguments are unpersuasive.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Mercy H. Sabila whose telephone number is (571)272-2562. The examiner can normally be reached Monday - Friday 5:00 am - 3:00 pm.
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/MERCY H SABILA/Examiner, Art Unit 1654
/LIANKO G GARYU/Supervisory Patent Examiner, Art Unit 1654
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