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 .
The Applicants’ Amendment to the Claims filed on January 19, 2026 is entered.
The Applicants’ Amendment to the Drawings filed on January 19, 2026 is entered.
The Applicants’ Amendment to the Specification filed on January 19, 2026 is entered.
The Sequence Listing filed on January 19, 2026 is acknowledged.
The Translation of Foreign Priority Documents filed on January 19, 2026 is acknowledged.
Claim 8 is new.
Claims 1-8 are pending and under examination.
Response to Amendment
All objections and rejections made in the previous Office Action and not repeated in this office action are withdrawn in view of the applicants’ submission filed on January 19, 2026.
Priority
This US18/247684 filed on 04/03/2023 which is a 371 of 371 of PCT/CN2020/124686 filed on 10/29/2020 which claims foreign priority benefit of CHINA 202010493951.2 filed on 06/03/2020.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
In accordance with 37 CFR 1.821(c) (b) (iii) the incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) must provide the size of the ASCII text file in bytes (not kilobytes as presently submitted).
Specification
The use of trade names or trademarks, such as the terms “CellTracker Green CMFDA” and “Invitrogen” (page 26, 34), and “Toxin Eraser” and “GeneScript” (page 34), and others, which are trade names or marks used in commerce, have been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized (each letter of the term should be capitalized) wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
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.
Currently amended claims 3 and 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.
Claim 3 recites “the step of tracing marked Annexin A5” in line 3. The antecedent basis for marked Annexin 5 is unclear because there is no prior reference to marked Annexin A5 in the claims.
Claim 6 recites “…wherein Annexin A5 exerts…” in lines 2-3. The antecedent basis for Annexin 5 is unclear because claim 6 depends from claims 1, and 4-5 and there is no prior reference to Annexin A5 in these claims.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Currently amended claims 1-7 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over WO-2010040147 to Yu & Krantz (April 8, 2010).
Claim interpretation: Generally, the intended use phrases in the claims are not afforded patentable weight for purpose of applying prior art to the claims.
Regarding claim 1, Yu et al discloses the use of phosphatidylserine in preparation of a drug for treatment of inflammatory bowel disease, wherein for the inflammatory bowel disease, phosphatidylserine serves as a target of the drug. For example, Yu et al disclose that the Annexin V compounds can be used for the treatment of Crohn’s disease. (See page 40, lines 27-29). For example, Yu et al disclose methods of making and using adducts in radio-labelling molecular imaging application, and treatment of Crohn’s disease are provided (See Abstract). Yu et al disclose that annexins are a group of calcium-binding structural proteins that play a role in the regulation of membrane trafficking, cellular adhesion, and cell signaling. (See page 37, lines 11-12). Annexins are characterized by reversible Ca2+-dependent intracellular membrane binding. (See page 37, lines 14-15). Annexins inherently bind to surfaces of phosphatidylserine-containing phospholipid bilayers either in the presence or Ca2+ or under conditions of low pH (pH 5-6). (See page 37, lines 18-20).
Regarding claim 2, Yu et al discloses that in the inflammatory bowel disease, phosphatidylserine of vascular endothelial cells is flipped from the intracellular membrane to the extracellular membrane, and the externalized phosphatidylserine serves as a marker of the inflammatory bowel disease. Yu et al disclose that apoptosis is a genetically defined cell death that involves activation of a core enzymatic machine consisting of cysteine proteases, called caspases. (See page 39, lines 26-28). Yu et al disclose that an early molecular event in apoptosis is the flipping of phosphatidylserine (PS) from the inner lipid bilayer to the outer layer of the plasma membrane. (See page 39, lines 28-29).
Regarding claim 3, Yu et al discloses that marked Annexin A5 is capable of being traced by phosphatidylserine in the extracellular membrane and indicating location of lesions and extent of the inflammatory bowel disease. Yu et al disclose that Annexin V has high therapeutic potential in humans and provides “a basis for the construction of various imaging agents as diagnostic tools and products” (see page 37, lines 19-34). Yu et al disclose annexin V has anticoagulatory effects that are mediated by the binding to negatively charged surface phospholipids (e.g., on activated platelets). (See page 38, lines 11-17). Yu et al disclose that Annexin V binds PS with extremely high affinity (Kd=7 nmol/L) as well as extremely high specificity, and has been used in vitro to identify apoptotic cells. (See page 39, lines 29-31). Yu et al disclose that Annexin V labeled with 18F is capable of detecting tumor cell death, thus serving as an early predictor of clinical response to anti-tumor drug therapy. (See page 39, lines 32-34).
Regarding claim 4, Yu et al disclose that the Annexin V compounds can be used for the treatment of Crohn’s disease. (See page 40, lines 27-29). Yu et al disclose the use of fluorescently labelled Annexin for use in survival assays for treatment of Crohn’s disease. (See page 43, lines 19-20). Yu et al discloses that the drug is screened by using phosphatidylserine as the target for the inflammatory bowel disease to obtain Annexin proteins having a high affinity to phosphatidylserine. Yu et al disclose that Annexin V binds PS with extremely high affinity (Kd=7 nmol/L) as well as extremely high specificity, and has been used in vitro to identify apoptotic cells. (See page 39, lines 29-31).
Regarding claims 5-6, Yu et al discloses that the drug exerts anti-inflammatory effects by binding to phosphatidylserine to inhibit inflammatory cell infiltration and block recruitment of colonic immune cells. Yu et al discloses that Annexin A5 exerts anti-inflammatory effects by binding to phosphatidylserine. Yu et al disclose that Annexin V has high therapeutic potential in humans and provides “a basis for the construction of various imaging agents as diagnostic tools and products” (see page 37, lines 19-34). Yu et al disclose annexin V has anticoagulatory effects that are mediated by the binding to negatively charged surface phospholipids (e.g., on activated platelets). (See page 38, lines 11-17). Yu et al disclose that Annexin V binds PS with extremely high affinity (Kd=7 nmol/L) as well as extremely high specificity, and has been used in vitro to identify apoptotic cells. (See page 39, lines 29-31). Yu et al disclose that Annexin V labeled with 18F is capable of detecting tumor cell death, thus serving as an early predictor of clinical response to anti-tumor drug therapy. (See page 39, lines 32-34).
Regarding claim 7, Yu et al discloses a method of modifying a drug that uses phosphatidylserine as a target for inflammatory bowel disease, comprising the step of: mutating Annexin A5 to enhance its binding ability to phosphatidylserine to improve anti-inflammatory effects thereof. Yu disclose site-specific modification of annexin proteins at their N-termini by transamination reactions to form adducts. Yu et al disclose using the resulting adducts of such modified proteins for screening and/or therapy of disorders such as Crohn’s disease. Yu et al teach that the annexin protein is annexin V protein. (ref claim 35). Yu et al disclose annexin V has anticoagulatory effects that are mediated by the binding to negatively charged surface phospholipids (e.g., on activated platelets). (See page 38, lines 11-17). Yu et al disclose that Annexin V labeled with 18F is capable of detecting tumor cell death, thus serving as an early predictor of clinical response to anti-tumor drug therapy. (See page 39, lines 32-34). Yu et al disclose the use of fluorescently labelled Annexin for use in survival assays for treatment of Crohn’s disease. (See page 43, lines 19-20).
Thus the Yu et al reference anticipates the limitations of the claims as presently written. However, in the alternative, Yu et al renders obvious the present claims.
The level of skill in the art was high before the effective filing date of the presently claimed invention. One of ordinary skill in the art would have been motivated to combine the elements of Yu et al for the rationale of making a marked Annexin V for using in preparation of a drug for treatment of IBS, where the drug is screened using PS as the target for the IBS to find drugs having a high affinity to PS, such as annexins, as disclosed by Yu et al. Note that intended use limitations are not generally afforded patentable weight for purpose of applying prior art. Note that “anti-inflammatory effects” exerted by Annexin A5 are construed to be inherent property. A product is not generally separable from its’ properties. Note that the instant specification does not include a limiting definition for the term mutating. Yu disclose site-specific modification of annexin proteins at their N-termini by transamination reactions to form adducts which is construed to meet the limitation of mutation.
It would have been obvious for one of ordinary skill in the art to combine the elements of Yu et al because Yu et al discloses all of the elements of the present claims as presently written. In view of the high skill level in the art it is considered that one of ordinary skill in the art having the Yu et al reference would have had a reasonable expectation of success to use phosphatidylserine in preparation of a drug or treatment of IBS, specifically Crohns’ disease, to arrive at the present claims.
Response to Arguments
The applicant’s arguments filed on 01/19/2026 have been fully considered but are unpersuasive. The applicants argue:
Independent claim 1 defines a process for preparing a drug for treatment of inflammatory bowel disease comprising the step of: targeting phosphatidylserine with the drug for the treatment of inflammatory bowel disease. On the other hand, Yu discloses chemical modification of proteins, including Annexins, at their N-termini to form adducts. Figs. 1-3 of Yu show mass spectral images depicting the modified proteins. Yu fails to provide any function verification of the modified proteins and therefore does not anticipate nor include a scope and content that teaches or suggests the process specifically defined in claim 1 including the step of targeting phosphatidylserine with the drug for the treatment of inflammatory bowel disease. Similarly, Yu does not disclose, as defined in claim 7, the step of mutating Annexin A5 to enhance its binding ability to phosphatidylserine to improve anti- inflammatory effects thereof. The Office Action states that the Abstract of Yu discloses methods of making and using adducts in radio-labeling, molecular imaging application, and treatments of disorders such as cancer, Crohn's disease, arthritis, atherothrombosis and plaque rupture.
However, this argument is unpersuasive because limitations must not be read into the claims. The specification does not provide a limiting definition for mutating a protein. Yu disclose site-specific modification of annexin proteins at their N-termini by transamination reactions to form adducts which is interpreted to meet the limitation of claim 7 of mutating Annexin A5. Yu et al disclose using the resulting adducts of such modified proteins for screening and/or therapy of disorders such as Crohn’s disease. Further, the applicants argue:
The Office Action further cites Page 40, lines 27-29 that discloses, "At present, there are no specific therapies for this disorder. In certain embodiments, the compounds of the present invention can be used for the treatment of Crohn's disease." However, Yu does not provide any verification through experiments that the compounds can indeed treat Crohn's disease. Rather, inferences are only made based on literature. Most of the relevant parts of Yu cited describe that Annexin V is a protein capable of identifying apoptosis and further provides explanations on why Annexin V can identify apoptosis. For example, Page 39, lines 26-34 states, "Apoptosis is a genetically defined cell death that involves activation of a core enzymatic machine consisting of cysteine proteases called caspases. An early molecular event in apoptosis is the flipping of phosphatidylserine (PS) from the inner lipid bilayer to the outer layer of the plasma membrane. Annexin V binds PS with extremely high affinity (kd=7 nmol/L), as well as specially, and has been used in vitro to identify apoptotic cells. Annexin V labeled with a position emitter such as 18F has been found to be capable of detecting tumor cell death, thereby serving as an early predictor of clinical responses to anti- tumor therapy." Therefore, Yu discloses that the use of Annexin V for treatment of diseases is based on its ability of identifying apoptosis.
However, the applicants’ argument is unpersuasive because the argument states “Yu discloses that the use of Annexin V for treatment of diseases is based on its ability of identifying apoptosis. Further, the argument cites the rejection for stating that “In certain embodiments, the compounds of the present invention can be used for the treatment of Crohn's disease" but argue that “Yu does not provide any verification through experiments that the compounds can indeed treat Crohn's disease”, but rather, inferences are only made based on literature. However, this argument is unpersuasive because arguments of counsel cannot take the place of evidence on the record.
With respect to U.S. Pub. 2006/0275834 mentioned in Yu, the content disclosed therein is also not relevant to the defined invention. US '834 discloses methods and compositions related to joint inflammation diseases. Although Crohn's disease is mentioned in paragraphs [0050], [0096], [0111] and [0354] and Annexin V is mentioned twice in paragraph [0380], it is not pertinent. Paragraphs [0050], [0096] and [0111] wherein Crohn's disease is mentioned, are related to osteoclast precursor cells (OCP), which can be a useful biomarker for Crohn's disease, see paragraph [0050] or the method for treating Crohn's disease is dependent on the measurement of OCP. The Crohn's disease mentioned in paragraph [0354] is related to an expansion of CD14*/CD11b+ cells. Annexin V mentioned in paragraph [0380] is used for conventional detection of apoptotic cells. Therefore, US '834 is not pertinent.
However, this argument is unpersuasive because intended use phrases are generally not afforded patentable weight for purpose of applying prior art to the claims. Further, the applicants argue:
In the claims, the Annexin A5 for the treatment of inflammatory bowel disease is totally different than the method described in Yu. The inventors have found that phosphatidylserine (PS) is present in a normal colon, and this is an important basis for targeted treatment of inflammatory bowel disease. For example, the inventors have found that through the overall distribution and metabolism of Annexin A5 in the body that in the capillaries of the colon of normal mice, PS is flipped from the intracellular membrane to the extracellular membrane. This phenomenon does not occur in the rectum. Still further, its presence is not related to apoptosis, see section 3.3.1 and FIGS. 13 and 14. The inventors have also found that the clinical data on human colitis shows that Annexin A5 expression is negatively correlated with the development of colitis, see section 1.3.1 as well as FIGS. 1 and 2. That is, the expression level of Annexin A5 in colonic tissues was significantly down-regulated with the development of colitis, and supplement of exogenous Annexin A5 recombinant protein was effective for treatment of the disease.
However, this argument is unpersuasive because it is not commensurate with the scope of the claims as written. For example, claim 1 is drawn to the active method step of targeting phosphatidylserine with a drug. Yu et al teach Annexin V which is a drug that inherently targets phosphatidylserine. Further, the applicants argue:
Another important aspect of invention is that the inventors discovered that Annexin A5 can be used to inhibit PS as a signal for inflammatory cell migration and infiltration, thereby reducing the adhesion and infiltration of inflammatory cells. In conclusion, the method of treating inflammatory bowel disease with Annexin A5 defined in the claims is distinguished from methods described in Yu wherein Annexin V recognizes apoptosis.
In conclusion, the method of treating inflammatory bowel disease with Annexin A5 defined in the claims is distinguished from methods described in Yu wherein Annexin V recognizes apoptosis.
Yu does not recognize nor teach or suggest PS of vascular endiothial cells flipped from the intracellular membrane to the extracellular membrane can serve as a marker of inflammatory bowel disease which can be targeted with Annexin V and patients with inflammatory bowel disease. In view of the above, it is respectfully submitted that Yu cannot anticipate nor teach or suggest the specifically defined methods set forth in the pending claims.
However, this argument is unpersuasive because arguments of counsel cannot take the place of evidence on the record. The intended use phrases in the claims are not generally afforded patentable weight for purpose of applying prior art. Note that claim 1 only recites IBS as intended use. Yu et al teaches Annexin V which inherently binds/targets phosphatidylserine in vascular endothelial cells.
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.
New claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Lawhon et al (CA 2 692 973 published 01/15/2009), in view of Kemerink et al (J Nucl Med 2001 Vol 42 pages 382 to 387), in view of Christin et al (US 20200191774 A1 published 06/18/2020, filed on 02/27/2018), in view of Kang et al (Nature Communications Feb 2020), in view of
Claim interpretation: Generally, the intended use phrases in the claim are not afforded patentable weight for purpose of applying prior art to the claim.
Kemerink et al disclose administering Annexin V to a patient. (See Title, Abstract, entire article). Kemerink et al disclose analyzing the level of Annexin V in colon tissue of the patient.
Lawhon et al disclose a method comprising analyzing an expression level of Annexin A5 in a patient tissue sample. (See para The patient sample includes a colon sample. (See para 2191).
Kang et al disclose that Annexin AV is a drug that inherently binds to phosphatidylserine in vascular endothelial cells. Kang et al discloses that as cells undergo apoptosis, the phosphatidylserine that normally resides in the inner leaflet of the plasma membrane undergoes relocalization to the outer plasma membrane where it becomes exposed to the extracellular environment and helps prevent undesirable inflammatory response. (See page 2, para 4). Kang et al disclose the use of Annexin AV treatment to patients following chemotherapy as a “promising immune checkpoint inhibitor for cancer treatment”. (See page 2, para 2). Kang et al suggest the use of Annexin AV for control of other diseases involving the association of PS expression and immunosuppressive apoptotic clearance. (See page 9, para bridging left and right col).
Christin et al disclose a process comprising administering Annexin V to cells. (See para 0031). Christin et al disclose assessing individual data points of the apoptosis marker being Annexin V or toxicity levels associated with the Annexin V expression marker. (See Fig 9, 11, para 0141, 0144, 0202, 0228, 0740, 1476, 1491, 1569-0570). Further, Christin et al disclose that the sample from which the cells are derived may be a colon sample. (See para 0576.) Further, Christin et al disclose that in some embodiments, the disease or condition is inflammatory bowel disease or Crohn’s disease. (See para 0328.)
The level of skill in the art was high before the effective filing date of the presently claimed invention.
One of ordinary skill in the art would have been motivated to combine the elements of the cited references, to administer Annexin A5 to a patient where the Annexin A5 targets phosphatidylserine in vascular endothelial cells, analyze an expression level of Annexin A5 in tissue of the patient including a colon tissue sample, and further treat the patient with Annexin A5.
It would have been obvious to one of ordinary skill in the art to do such because the cited references show it was known to treat a patient with Annexin A5 and to analyze an expression level of Annexin A5 in a colon sample of a patient.
In view of the high skill level in the art it is considered that one of ordinary skill in the art having the cited references before the effective filing date of the presently claimed invention would have had a reasonable expectation of success to combine the elements of the cited references to arrive at the presently claimed invention.
Conclusion
No claim is allowed.
Related art which may be applied in a future office action if appropriate:
Ewing et al 2011.
Li et al (Bioconjugate Chem 2008 Vol 19 pages 1684 to 1688).
Horta et al “Analysis of the Association between Fatigue and the Plasma Lipidomic Profile of Inflammatory Bowel Disease Patients” (J Proteome Res 2021 Jan 1 2021; Vol 20, No 1: pages 381-392; of record). (post-filing art). Horta et al disclose that phosphatidylserine is a biomarker for IBS in patient. (See Title; Abstract).
Iwatani et al in “Novel mass spectrometry-based comprehensive lipidomic analysis of plasma from patients with inflammatory bowel disease” J Gastroenterol Hepatol 2020 Aug; 35(8):1355-1364. Epub 2020 Apr 23; of record). Iwatani et al disclose that phosphatidylserine is a biomarker for IBS in a patient with Crohn’s disease. (See Title; Abstract).
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 CATHERINE S HIBBERT whose telephone number is (571)270-3053. The examiner can normally be reached M-F 8:00-5:00.
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/CATHERINE S HIBBERT/Primary Examiner, Art Unit 1658