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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 10/09/2025 has been entered.
Priority
This application is a CIP of 16/742,131 filed 01/14/2020 now Patent number 11357823.
Claim Status
Claims 1-26 are pending. Claim 1 is amended. Claims 1-26 are being examined on the merits in this office action.
Claim Objections
Claim 1 is objected to because of the following informalities:
Claim 1 contains a hyphen between the articles “of” and “Annexin” on line 6.
Further, claim 1 should be amended to included the article “by” between the words “deficit” and “about”, and between “evaluation” and “about”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-24 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a NEW MATTER rejection.
The response filed 09/12/2025 has introduced NEW MATTER into the claims. The newly added/amended Claim(s) 1 recites “equivalent to a dose of 0.2 mg/kg in a rat”. The response did not specifically and adequately point out where support for newly added/amended Claim(s) 1 could be found in the originally filed disclosure.
Although the PTO has the initial burden of presenting evidence or reasons why persons skilled in the art would not recognize in the disclosure a description of the invention defined by the claims, when filing an amendment an applicant should show support in the original disclosure for new or amended claims. See MPEP 714.02 and 2163.06 (“Applicant should therefore specifically point out the support for any amendments made to the disclosure.”).
The amended claims now recites limitations, which were not clearly disclosed in the specification as filed, and now change the scope of the instant disclosure as filed. Such limitations recited in newly amended claim, which did not appear in the specification, as filed, introduce new concepts and violate the description requirement of the first paragraph of 35 U.S.C 112. Examiner in unsure what the recited dose is equivalent to, or to what subject. This is not disclosed in the instant specification and thus constitutes new matter. Applicant is required to provide sufficient written support for the limitations recited in the present claims in the specification, or claims as-filed, or remove these limitations from the claims in response to this Office Action.
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, and 9-13 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 1 recites the limitation "identifying a subject having TBI or suspected as having TBI" in line 3-4. It is unclear how one can look at a subject and suspect or identify that the subject has TBI.
Claim 9 recites “…composition is administered in a period from the time of the TBI to 4 weeks”. Examiner notes the recitation of the time period is inconsistent with what is recited in the independent claim 1. Claim 10 has a similar problem.
Claim 11 recites “…wherein the therapeutically effective amount of Annexin A5 is between about 0.01 mg/kg and about 0.5 mg/kg”. It is unclear if the recited amount is the amount administered in a rat or the equivalent dose. Claims 12-13 have a similar problem.
Claim Rejections - 35 USC § 103 - New
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 1-26 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. 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 9-10, Feng teaches Annexin A5 can be administered on a daily basis, every two days, every three days, every four days, every five days, every six days, a weekly basis, a monthly basis or any set number of days or weeks there-between, every two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, twelve months [0113] and that annexin A5 was administered four hours after saline treatment [0128].
Regarding claims 11-13, Feng teaches that Annexin A5 is administered at a dose range from about 0.1 μg to 20 mg/kg, more typically from about 1 to 10 mg/kg, and most typically from about 1 to 5 mg/kg or less than 0.1 μg/kg, or equal to or less than 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1 mg/kg, or an or equal to 0.1 mg/kg per day (e.g., less than or equal to 0.09, 0.08, 0.07, 0.06, 0.5, 0.04, 0.03, 0.02 or 0.01 mg/kg [0113].
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]).
Conclusion
No claims are allowed.
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