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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 June 3, 2026 has been entered.
The Applicants’ Amendment to the Claims filed on June 3, 2026 is entered.
The Applicants’ Amendment to the Specification filed on June 3, 2026 is entered.
Claims 1-7 are cancelled. Claim 9-12 are new.
Claims 8-12 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All objections and rejections made in the previous Office Action and not repeated in this office action are withdrawn in view of the applicants’ submission filed on June 3, 2026.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.
Claim Rejections - 35 USC § 103 – new grounds of rejection
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.
Claims 8-12 are 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 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 WO-2010040147 to Yu & Krantz (April 8, 2010), and Ewing et al “Annexin A5 Therapy Attenuates Vascular Inflammation and Remodeling and Improves Endothelial Function in Mice” (Arteriosclerosis, Thrombosis, and Vascular Biology Vol 31, No 1, January 2011, pages 95-101; of record).
Claim interpretation: Generally, the intended use phrases in the claim are not afforded patentable weight for purposes of applying prior art to the claim.
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.)
Regarding claim 8, 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). 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). 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).
Regarding claim 9 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 10, 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 11, 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 12, Ewing et al discloses that Annexin A5 is administered at a dose of 1 mg/kg per day which meets the limitation of 0.05 mg/kg to 0.10 mg/kg. (See Abstract, “Methods and Results”, line 1).
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 for the rationale of treating the inflammatory disease of inflammatory bowel disease.
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. Further, Yu et al suggest 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.
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.
Response to Arguments
The applicant’s arguments filed on June 3, 2026 have been fully considered as they may relate to this new grounds of rejection but are unpersuasive. The applicants argue:
Independent claim 8 is based upon the unexpected discovery of a method for treating inflammatory bowel disease, comprising the steps of: administering Annexin A5 to a patient which targets and binds to phosphatidylserine of vascular endothelial cells; analyzing an expression level of the Annexin A5 in colon tissue of the patient; and further treating the patient with the Annexin A5 based on the analysis. None of the cited references include a scope and content that teaches or suggests the method step of further treating a patient with Annexin V based on the analysis of the expression level of the Annexin V in colon tissue of the patient. Based on the finding that the expression of Annexin A5 in the inflammatory colonic tissues was significantly downregulated and administration of exogenous Annexin A5 is effective in the treatment of inflammatory bowel disease, the inventors had made the present invention. Independent claim 8 intends to protect a method for treating inflammatory bowel disease, comprising the steps of: administering Annexin A5 to a patient which targets and binds to phosphatidylserine of vascular endothelial cells; analyzing an expression level of the Annexin A5 in colon tissue of the patient; and further treating the patient with the Annexin A5 based on the analysis.
Kang discloses, as set forth in the title, Annexin A5 as an immune checkpoint inhibitor and tumor-homing molecule for cancer treatment. As set forth on page 2, second column, the Annexin A5 is utilized in a treatment along with cisplatin and HPV16-E7 long peptide. In fact, Kang teaches the use of Annexin A5 in the treatment of patients after chemotherapy. The principle of the use is that Annexin A5 can block the PS-mediated immunosuppressive signal, thereby reactivating the tumor immune microenvironment. This is essentially different in mechanism from the use of Annexin A5 in treating colitis of the claimed invention wherein Annexin A5 exerts anti-inflammatory effects and inhibits immune activation by binding to PS exposed on the vascular endothelial cells in the colon region. Therefore, to one of ordinary skill in the art, there is no suggestion for analyzing the expression level of Annexin A5 in colon tissue with a patient and then further treating the patient with additional Annexin A5 based on the analysis. Similarly, Christin administers T-cell compositions to patients. Annexin A5 is only utilized as a marker, see for example paragraph [0012]. There is no teaching or suggestion of the steps set forth in claim 8.
Although Yu & Krantz, the reference cited in this Office Action with respect to cancelled claims 1-7, is not used in the final Office Action against claim 8, Applicant would like to emphasize that Yu & Krantz is not pertinent. As disclosed in page 2, lines 27-31, Yu & Krantz provides chemical modification of proteins, e.g. annexin proteins, at their N-termini via transamination reactions which mediate the formation of homogeneous adducts which are derived from bifunctional entities such as bis-alkoxyl amines capable of installing biologically useful ligands or latent reactive groups on protein frameworks. Therefore, the activity of the adducts in Yu & Krantz comes from the chemical modification at the N-terminus. The adducts have additional active groups added at the N-terminus, which possess extra biological activity and functions. In the claimed invention, Annexin A5 is used without the need for additional N-terminal chemical modification, but still has excellent inhibitory or therapeutic activity for IBD. In conclusion, claim 8 possesses an inventive step and is not at all obvious over the references cited in the Office Action. On the basis that claim 8 is inventive, claims 9- 12 depending from claim 8 each are also inventive and not obvious.
However, the applicants argument is unpersuasive as it may pertain to this new grounds of rejection. First, the 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. Yu et al teaches Annexin V which inherently binds/targets phosphatidylserine in vascular endothelial cells. For example, claim 8 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.
Second, the argument that Yu et al the activity of the adducts in Yu & Krantz comes from the chemical modification at the N-terminus, which possess extra biological activity and functions and that “the claimed invention, Annexin A5 is used without the need for additional N-terminal chemical modification, but still has excellent inhibitory or therapeutic activity for IBD” is unpersuasive because the argument is not commensurate with the scope of the present claims. Present claims use open claim language “comprising” and do not limit the Annexin A5.
Further, 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).
Further, the argument that Kang teaches the use of Annexin A5 in the treatment of patients after chemotherapy is unpersuasive. 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).
Conclusion
No claim is allowed.
Related art which may be applied in a future office action if appropriate:
Hyoung-Seok Baek et al (2017 vol 8 No 43 pages 74263 to 74275).
Li et al (Bioconjugate Chem 2008 Vol 19 pages 1684 to 1688; of record).
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).
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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Melissa Fisher can be reached at 571-270-7430. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
CATHERINE S. HIBBERT
Primary Examiner
Art Unit 1658
/CATHERINE S HIBBERT/Primary Examiner, Art Unit 1658
Prosecution Insights