DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Amendment after Non-final office action filed on 2/23/2026 is acknowledged.
3. Claim filed on 2/23/2026 is acknowledged.
4. Claims 4, 10, 13, 16, 19, 21, 23, 25, 28 and 29 have been cancelled.
5. Claims 1-3, 5-9, 11, 12, 14, 15, 17, 18, 20, 22, 24, 26 and 27 are pending in this application.
6. Claims 1-3, 5-9, 11, 12, 14, 15, 17 and 18 remain withdrawn from consideration pursuant to 37 CFR 1.142(b), as being drawn to non-elected inventions, there being no allowable generic or linking claim.
7. Applicant elected without traverse Group 3 (claims 20, 22, 24, 26, 27 and 29) and elected alteplase as species of fibrinolytic in the reply filed on 9/2/2025. Applicant further elected on the phone annexin A2 consisting of the amino acid sequence of SEQ ID NO: 1 with N62A substitution as species of annexin A2; and a subject having fibrinolytic shutdown as species of subject on 9/17/2025.
Restriction requirement was deemed proper and made FINAL in the previous office action. Group 3 is drawn to a method of enhancing clot dissolution in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of an annexin A2 and at least one fibrinolytic agent; wherein the at least one fibrinolytic agent is selected from the group consisting of: streptokinase, urokinase, anistreplase, alteplase, reteplase, and tenecteplase. A search was conducted on the elected species; and prior art was found. Claims 20, 22, 24, 26 and 27 are examined on the merits in this office action.
Withdrawn Objections and Rejections
8. Objection to the specification is hereby withdrawn in view of Applicant’s amendment to the specification.
9. Objection to claims 24, 26, 27 and 29 is hereby withdrawn in view of Applicant’s amendment to the claim.
10. Rejection to claims 24 and 27 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph is hereby withdrawn in view of Applicant’s amendment to the claim.
11. Rejection to claims 20 and 27 under 35 U.S.C. 102(a)(1) as being anticipated by Walvick et al (Stroke, 2011, 42, pages 1110-1115), and as evidenced by Flood et al (CHAPTER 38 Bleeding and Thrombosis, from Nelson Pediatric Symptom-Based Diagnosis, 2018, pages 682-700) is hereby withdrawn in view of Applicant’s amendment to the claim.
12. Rejection to claims 20, 24, 26 and 27 under 35 U.S.C. 102(a)(1) as being anticipated by Wang (US 2015/0105322 A1, filed with IDS), and as evidenced by Flood et al (CHAPTER 38 Bleeding and Thrombosis, from Nelson Pediatric Symptom-Based Diagnosis, 2018, pages 682-700) is hereby withdrawn in view of Applicant’s amendment to the claim.
13. Rejection to claims 20, 22, 24, 26 and 27 under 35 U.S.C. 103 as being unpatentable over Wang (US 2015/0105322 A1, filed with IDS), and as evidenced by Flood et al (CHAPTER 38 Bleeding and Thrombosis, from Nelson Pediatric Symptom-Based Diagnosis, 2018, pages 682-700), and in view of Elliott et al (International Journal of Stroke, 2015, 10, pages 194-201) is hereby withdrawn in view of Applicant’s amendment to the claim.
14. Rejection to claims 20, 24, 26 and 27 on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 10 and 11 of US patent 9314500 B2 in view of Wang (US 2015/0105322 A1, filed with IDS), and as evidenced by Flood et al (CHAPTER 38 Bleeding and Thrombosis, from Nelson Pediatric Symptom-Based Diagnosis, 2018, pages 682-700) is hereby withdrawn in view of Applicant’s amendment to the claim.
15. Rejection to claims 20, 22, 24, 26 and 27 on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 10 and 11 of US patent 9314500 B2 in view of Wang (US 2015/0105322 A1, filed with IDS) and Elliott et al (International Journal of Stroke, 2015, 10, pages 194-201), and as evidenced by Flood et al (CHAPTER 38 Bleeding and Thrombosis, from Nelson Pediatric Symptom-Based Diagnosis, 2018, pages 682-700) is hereby withdrawn in view of Applicant’s amendment to the claim.
Maintained/Revised Objections
16. (Revised due to Applicant’s amendment to the claim) Claim 20 remains objected to for the following minor informality: Applicant is suggested to amend claim 20 as “…a therapeutically effective amount of an annexin A2 and at least one fibrinolytic agent; and wherein the at least one fibrinolytic agent is selected from the group consisting of streptokinase, urokinase…”.
Response to Applicant's Arguments
17. Applicant’s amendment to claim 20 introduces additional minor issues into instant claim 20. Therefore, claim 20 remains objected.
Maintained/Revised Rejections
Claim Rejections - 35 U.S.C. § 103
18. 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 of this title, 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.
19. The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
20. Please note: during the search for the elected species, prior art was found for the non-elected species of subject.
(Revised due to Applicant’s amendment to the claim) Claims 20, 24, 26 and 27 remain rejected under 35 U.S.C. 103 as being unpatentable over Wang (US 2015/0105322 A1, filed with IDS), and as evidenced by Flood et al (CHAPTER 38 Bleeding and Thrombosis, from Nelson Pediatric Symptom-Based Diagnosis, 2018, pages 682-700, cited and enclosed in the previous office action), and in view of Anderson et al (N Engl J Med, 2016, 374, pages 2313-2323, cited and enclosed in the previous office action).
The instant claims 20, 24, 26 and 27 are drawn to a method of enhancing clot dissolution in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of an annexin A2 and at least one fibrinolytic agent; wherein the at least one fibrinolytic agent is selected from the group consisting of: streptokinase, urokinase, anistreplase, alteplase, reteplase, and tenecteplase.
Wang, throughout the patent, teaches a non-N-glycosylated human Annexin A2 comprising SEQ ID NO: 1, wherein the amino acid at position 62 is not Asparagine (N), and/or the amino acid at position 64 is neither Threonine (T) nor Serine (S), including human annexin A2-6xHis (SEQ ID NO: 4) with N62A substation; and a method of treating ischemic stroke due to clot formation in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of such non-N-glycosylated human annexin A2 in combination with a therapeutically effective amount of tPA (Tissue Plasminogen Activator), wherein the non-N-glycosylated human annexin A2 enhances the function of tPA, and wherein the ischemic stroke can be acute ischemic stroke, for example, Abstract; Figure 1A; page 1, paragraphs [0003], [0004], [0006], [0009]-[0011] and [0016]; page 2, paragraph [0022]; page 3, paragraphs [0030] and [0031]; and page 6, paragraph [0047]. And as evidenced by Flood et al, tissue plasminogen activator (tPA) in the method in Wang is a fibrinolytic agent (see for example, the paragraph bridging pages 699 and 700). Wang further teaches removing the purification tag after purifying the non-N-glycosylated human Annexin A2, for example, page 4, paragraph [0033]. The non-N-glycosylated human Annexin A2 consisting of SEQ ID NO: 1 with N62A substitution or consisting of SEQ ID NO: 4 with both N62A substitution and removing the 6Xhis tag reads on annexin A2 consisting of the amino acid sequence of instant SEQ ID NO: 1 with N62A substitution as the elected species of annexin A2; and meets the limitation of annexin A2 recited in instant claims 20, 24 and 26. Wang also teaches the dose of annexin A2 required for enhancing the function of tPA in vivo is 5 mg/kg, for example, page 10, paragraph [0077]. It meets the limitation of instant claim 27. Furthermore, in view of the teachings of Wang as a whole, one of ordinary skilled in the art would reasonably expect and at once envision a method of treating ischemic stroke due to clot formation in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a non-N-glycosylated human annexin A2 in combination with a therapeutically effective amount of tPA (a fibrinolytic agent), wherein the non-N-glycosylated human annexin A2 enhances the function of tPA, wherein the non-N-glycosylated human Annexin A2 comprises SEQ ID NO: 1 with N62A substitution, such as human annexin A2 consisting of SEQ ID NO: 1 with N62A substitution or human annexin A2-6xHis (SEQ ID NO: 4) with N62A substation, wherein the non-N-glycosylated human annexin A2 is administering at a concentration of 5 mg/kg, and wherein the ischemic stroke can be acute ischemic stroke.
The difference between the reference and instant claims 20, 24, 26 and 27 is that the reference does not explicilty teach alteplase as the elected species of fibrinolytic agent; and the limitations of “enhancing clot dissolution” and “wherein the at least one fibrinolytic agent is selected from the group consisting of: streptokinase, urokinase, anistreplase, alteplase, reteplase, and tenecteplase” recited in instant claim 20.
However, Anderson et al teach alteplase as an approved recombinant tissue-type plasminogen activator (tPA) that can be used to treat acute ischemic stroke, for example, Title; and page 2314, left column, the 1st paragraph. It reads on alteplase as the elected species of fibrinolytic.
Therefore, it would have been obvious to one of ordinary skilled in the art to combine the teachings of Wang and Anderson et al to develop a method of treating ischemic stroke due to clot formation in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a non-N-glycosylated human annexin A2 in combination with a therapeutically effective amount of alteplase (an approved recombinant tPA), wherein the non-N-glycosylated human Annexin A2 comprises SEQ ID NO: 1 with N62A substitution, such as human annexin A2 consisting of SEQ ID NO: 1 with N62A substitution or human annexin A2-6xHis (SEQ ID NO: 4) with N62A substation, wherein the non-N-glycosylated human annexin A2 is administering at a concentration of 5 mg/kg, and wherein the ischemic stroke is acute ischemic stroke.
With regards to the limitation “a method of enhancing clot dissolution in a subject” recited in instant claim 20, this is a result-oriented limitation. In the instant case, the method developed from the combined teachings of Wang and Anderson et al above comprises the same active method step, i.e., the same patient population and the same compounds, therefore, administering the same compounds to the same patient population would lead to the same effect, i.e., enhancing clot dissolution in the subject. And since the USPTO lacks the experimental facilities to make a further determination, the burden is on the Applicant to prove the otherwise.
One of ordinary skilled in the art would have been motivated to combine the teachings of Wang and Anderson et al to develop a method of treating ischemic stroke due to clot formation in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a non-N-glycosylated human annexin A2 in combination with a therapeutically effective amount of alteplase (an approved recombinant tPA), wherein the non-N-glycosylated human Annexin A2 comprises SEQ ID NO: 1 with N62A substitution, such as human annexin A2 consisting of SEQ ID NO: 1 with N62A substitution or human annexin A2-6xHis (SEQ ID NO: 4) with N62A substation, wherein the non-N-glycosylated human annexin A2 is administering at a concentration of 5 mg/kg, wherein the ischemic stroke is acute ischemic stroke, and wherein the treatment results in enhancing clot dissolution in the subject, because Anderson et al teach alteplase as an approved recombinant tissue-type plasminogen activator (tPA) that can be used to treat acute ischemic stroke. The method developed from the combined teachings of Wang and Anderson et al is a simple substitution of one known element for another to obtain predictable results (see MPEP § 2143 I).
A person of ordinary skilled in the art would have reasonable expectation of success in combining the teachings of Wang and Anderson et al to develop a method of treating ischemic stroke due to clot formation in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a non-N-glycosylated human annexin A2 in combination with a therapeutically effective amount of alteplase (an approved recombinant tPA), wherein the non-N-glycosylated human Annexin A2 comprises SEQ ID NO: 1 with N62A substitution, such as human annexin A2 consisting of SEQ ID NO: 1 with N62A substitution or human annexin A2-6xHis (SEQ ID NO: 4) with N62A substation, wherein the non-N-glycosylated human annexin A2 is administering at a concentration of 5 mg/kg, wherein the ischemic stroke is acute ischemic stroke, and wherein the treatment results in enhancing clot dissolution in the subject.
Response to Applicant's Arguments
21. Applicant argues that “A person of ordinary skill in the art would not have been motivated to combine the teaching of Wang with the disclosure of Anderson et al, with any reasonable expectation of success.”
22. Applicant's arguments have been fully considered but have not been found persuasive.
In response to Applicant's arguments about instant rejection, the Examiner agrees that none of the cited references individually teaches or suggests the method recited in instant claims 20, 24, 26 and 27; and none of the cited references anticipates the method recited in instant claims 20, 24, 26 and 27. However, the Examiner would like to point out that instant claims 20, 24, 26 and 27 are rejected under 35 U.S.C. 103 (obviousness type), and the rejection is based on the combined teachings of Wang and Anderson et al, it is not necessary for each of the cited references to teach all the limitations of instant claims. Furthermore, the Examiner would like to point out that the MPEP states "One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references…" (see MPEP § 2145 IV).
In response to Applicant’s arguments that a person of ordinary skill in the art would not have been motivated to combine the teaching of Wang with the disclosure of Anderson et al with any reasonable expectation of success: The Examiner would like to point out that as stated in Section 20 above, Wang explicitly teaches a method of treating ischemic stroke due to clot formation in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of such non-N-glycosylated human annexin A2 in combination with a therapeutically effective amount of tPA (Tissue Plasminogen Activator), wherein the non-N-glycosylated human annexin A2 enhances the function of tPA, and wherein the ischemic stroke can be acute ischemic stroke. And Anderson et al explicitly teach alteplase as an approved recombinant tissue-type plasminogen activator (tPA) that can be used to treat acute ischemic stroke. The Examiner understands that both Wang and Anderson et al discuss potential adverse effects of tPA. However, in the instant case, the Examiner would like to point out that: First, Wang explicilty teaches co-administration of AnnexinA2 lowers the effective concentration of tPA required to convert plasminogen to plasmin, reduces the risk of neurotoxic and hemorrhagic complications, and prolongs the treatment window (see for example, page 1, paragraph [0004]). Second, Anderson et al explicitly teach “the Japanese drug safety authority has approved the use of alteplase at a dose of 0.6 mg per kilogram after an uncontrolled, open-label study showed that this dose resulted in equivalent clinical outcomes and a lower risk of intracerebral hemorrhage than that reported in published studies in which the 0.9-mg-per-kilogram dose was used.” (see page 2314, left column, the 1st paragraph). Third, a method of enhancing clot dissolution in a subject suffering from stoke with a combination of annexin A2 (rA2) and tPA is known in the art, as disclosed in both Wang and Walvick et al (Stroke, 2011, 42, pages 1110-1115, cited and enclosed in the previous office action).
Taken all these together, considering the state of art and in view of the combined teachings of Wang and Anderson et al as set forth in Section 20 above, one of ordinary skilled in the art would have been motivated to develop the method recited in instant claims 20, 24, 26 and 27; and a person of ordinary skilled in the art would have reasonable expectation of success in developing the method recited in instant claims 20, 24, 26 and 27. Furthermore, as stated in Section 20 above, the method developed from the combined teachings of Wang and Anderson et al is a simple substitution of one known element for another to obtain predictable results (see MPEP § 2143 I). In addition, with regards to the expectation of success, the MPEP states: “Absolute predictability is not a necessary prerequisite to a case of obviousness. Rather, a degree of predictability that one of ordinary skill would have found to be reasonable is sufficient. The Federal Circuit concluded that “[g]ood science and useful contributions do not necessarily result in patentability.” Id. at 1364, 83 USPQ2d at 1304.” (see MPEP § 2145).
Taken all these together, the rejection is deemed proper and is hereby maintained.
The Walvick et al reference is cited only for the purpose of rebutting Applicant's arguments, therefore, it is not cited as a prior art reference.
Obviousness Double Patenting
23. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the claims at issue are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); and In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
24. (Revised due to Applicant’s amendment to the claim) Claims 20, 24, 26 and 27 remain rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 10 and 11 of US patent 9314500 B2, and in view of Wang (US 2015/0105322 A1, filed with IDS), and as evidenced by Flood et al (CHAPTER 38 Bleeding and Thrombosis, from Nelson Pediatric Symptom-Based Diagnosis, 2018, pages 682-700, cited and enclosed in the previous office action), and further in view of Anderson et al (N Engl J Med, 2016, 374, pages 2313-2323, cited and enclosed in the previous office action).
25. Instant claims 20, 24, 26 and 27 are drawn to a method of enhancing clot dissolution in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of an annexin A2 and at least one fibrinolytic agent; wherein the at least one fibrinolytic agent is selected from the group consisting of: streptokinase, urokinase, anistreplase, alteplase, reteplase, and tenecteplase.
26. Claims 10 and 11 of US patent 9314500 B2 are drawn to a method of treating a subject who has a vascular disorder associated with thrombus formation, the method comprising administering to the subject a therapeutically effective amount of the non-N-glycosylated human annexin A2 comprising SEQ ID NO: 1, wherein the amino acid at position 62 is alanine (A) or glycine (G); and/or the amino acid at position 64 is neither threonine (T) nor Serine (S).
27. The difference between the method recited in claims 10 and 11 of US patent 9314500 B2 and the method recited in instant claims 20, 24, 26 and 27 is that the method recited in claims 10 and 11 of US patent 9314500 B2 does not teach the at least one fibrinolytic recited in instant claim 20; and the limitations of instant claim 27.
However, in view of the combined teachings of Wang and Anderson et al as set forth in Section 20 above, it would have been obvious to one of ordinary skilled in the art to modify the method recited in claims 10 and 11 of US patent 9314500 B2 and develop the method recited in instant claims 20, 24, 26 and 27.
Response to Applicant's Arguments
28. Applicant argues that “Claims 10 and 11 of U.S. Patent No. 9,314,500 neither teach nor suggest a method of enhancing clot dissolution as recited in amended claim 20, from which claims 24, 26, 27, and 29 depend. Wang and Anderson et al, as evidenced by Flood et al do not cure the deficiencies of U.S. Patent No. 9,315,500. For the reasons provided in the remarks related to the rejection under 35 U.S.C. § 103 above, Applicant requests reconsideration and withdrawal of this rejection.”
29. Applicant's arguments have been fully considered but have not been found persuasive.
In response to Applicant’s arguments about instant rejection, the Examiner understands that claims 10 and 11 of US patent 9314500 B2 do not teach or suggest the method recited in instant claims 20, 24, 26 and 27. However, in the instant case, the Examiner would like to point out that this ODP rejection is based on further in view of the combined teachings of Wang and Anderson et al as set forth in Section 20 above. Therefore, it is not necessary for claims 10 and 11 of US patent 9314500 B2 to teach or suggest the method recited in instant claims 20, 24, 26 and 27. Furthermore, Applicant’s arguments related to the rejection under 35 U.S.C. § 103 have been addressed in Section 22 above.
Taken all these together, the double patenting rejection is deemed proper. And until a proper terminal disclaimer is filed and approved by the Office, the double patenting rejection is hereby maintained.
New Rejections
Claim Rejections - 35 U.S.C. § 103
30. 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 of this title, 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.
31. The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
32. Claims 20, 22, 24, 26 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Wang (US 2015/0105322 A1, filed with IDS), and as evidenced by Flood et al (CHAPTER 38 Bleeding and Thrombosis, from Nelson Pediatric Symptom-Based Diagnosis, 2018, pages 682-700, cited and enclosed in the previous office action), and in view of Anderson et al (N Engl J Med, 2016, 374, pages 2313-2323, cited and enclosed in the previous office action), and further in view of Elliott et al (International Journal of Stroke, 2015, 10, pages 194-201, cited and enclosed in the previous office action).
The instant claims 20, 22, 24, 26 and 27 are drawn to a method of enhancing clot dissolution in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of an annexin A2 and at least one fibrinolytic agent; wherein the at least one fibrinolytic agent is selected from the group consisting of: streptokinase, urokinase, anistreplase, alteplase, reteplase, and tenecteplase.
The rejection to instant claims 20, 24, 26 and 27 under 35 U.S.C. 103 as being unpatentable over Wang (US 2015/0105322 A1, filed with IDS), and as evidenced by Flood et al (CHAPTER 38 Bleeding and Thrombosis, from Nelson Pediatric Symptom-Based Diagnosis, 2018, pages 682-700, cited and enclosed in the previous office action), and in view of Anderson et al (N Engl J Med, 2016, 374, pages 2313-2323, cited and enclosed in the previous office action) has been set forth in Section 20 above.
The difference between the rejection set forth in Section 20 above and instant claims 20, 22, 24, 26 and 27 is that the rejection set forth in Section 20 above does not explicilty teach a subject having fibrinolytic shutdown as the elected species of subject; and the limitation of instant claim 22.
However, Elliott et al, throughout the literature, teach patient with acute ischemic stroke has LY30 of 0 (0–0.4), and tPA treatment increases LY30 in such patient to 94.4 (15.2–95.3), for example, page 199, Table 3. And as evidenced by instant specification, the acute ischemic stroke patient with LY30 of 0 (0–0.4) in Elliott et al is a subject having fibrinolytic shutdown (see page 6, paragraph [39] of instant specification). It reads on a subject having fibrinolytic shutdown as the elected species of subject. Therefore, it would have been obvious to one of ordinary skilled in the art to combine the teachings of Wang, Anderson et al and Elliott et al to develop a method of treating ischemic stroke due to clot formation in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a non-N-glycosylated human annexin A2 in combination with a therapeutically effective amount of alteplase (an approved recombinant tPA), wherein the non-N-glycosylated human Annexin A2 comprises SEQ ID NO: 1 with N62A substitution, such as human annexin A2 consisting of SEQ ID NO: 1 with N62A substitution or human annexin A2-6xHis (SEQ ID NO: 4) with N62A substation, wherein the non-N-glycosylated human annexin A2 is administering at a concentration of 5 mg/kg, and wherein the ischemic stroke is acute ischemic stroke, including acute ischemic stroke having fibrinolytic shutdown.
With regards to the limitation “a method of enhancing clot dissolution in a subject” recited in instant claim 20, this is a result-oriented limitation. In the instant case, the method developed from the combined teachings of Wang, Anderson et al and Elliott et al above comprises the same active method step, i.e., the same patient population and the same compounds, therefore, administering the same compounds to the same patient population would lead to the same effect, i.e., enhancing clot dissolution in the subject. And since the USPTO lacks the experimental facilities to make a further determination, the burden is on the Applicant to prove the otherwise.
One of ordinary skilled in the art would have been motivated to combine the teachings of Wang, Anderson et al and Elliott et al to develop a method of treating ischemic stroke due to clot formation in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a non-N-glycosylated human annexin A2 in combination with a therapeutically effective amount of alteplase (an approved recombinant tPA), wherein the non-N-glycosylated human Annexin A2 comprises SEQ ID NO: 1 with N62A substitution, such as human annexin A2 consisting of SEQ ID NO: 1 with N62A substitution or human annexin A2-6xHis (SEQ ID NO: 4) with N62A substation, wherein the non-N-glycosylated human annexin A2 is administering at a concentration of 5 mg/kg, wherein the ischemic stroke is acute ischemic stroke, including acute ischemic stroke having fibrinolytic shutdown, and wherein the treatment results in enhancing clot dissolution in the subject, because Elliott et al, throughout the literature, teach patient with acute ischemic stroke has LY30 of 0 (0–0.4), and tPA treatment increases LY30 in such patient to 94.4 (15.2–95.3).
A person of ordinary skilled in the art would have reasonable expectation of success in combining the teachings of Wang, Anderson et al and Elliott et al to develop a method of treating ischemic stroke due to clot formation in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a non-N-glycosylated human annexin A2 in combination with a therapeutically effective amount of alteplase (an approved recombinant tPA), wherein the non-N-glycosylated human Annexin A2 comprises SEQ ID NO: 1 with N62A substitution, such as human annexin A2 consisting of SEQ ID NO: 1 with N62A substitution or human annexin A2-6xHis (SEQ ID NO: 4) with N62A substation, wherein the non-N-glycosylated human annexin A2 is administering at a concentration of 5 mg/kg, wherein the ischemic stroke is acute ischemic stroke, including acute ischemic stroke having fibrinolytic shutdown, and wherein the treatment results in enhancing clot dissolution in the subject.
Obviousness Double Patenting
33. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the claims at issue are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); and In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
34. Claims 20, 22, 24, 26 and 27 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 10 and 11 of US patent 9314500 B2, and in view of Wang (US 2015/0105322 A1, filed with IDS), and as evidenced by Flood et al (CHAPTER 38 Bleeding and Thrombosis, from Nelson Pediatric Symptom-Based Diagnosis, 2018, pages 682-700, cited and enclosed in the previous office action), and further in view of Anderson et al (N Engl J Med, 2016, 374, pages 2313-2323, cited and enclosed in the previous office action) and Elliott et al (International Journal of Stroke, 2015, 10, pages 194-201, cited and enclosed in the previous office action).
35. Instant claims 20, 22, 24, 26 and 27 are drawn to a method of enhancing clot dissolution in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of an annexin A2 and at least one fibrinolytic agent; wherein the at least one fibrinolytic agent is selected from the group consisting of: streptokinase, urokinase, anistreplase, alteplase, reteplase, and tenecteplase.
36. Claims 10 and 11 of US patent 9314500 B2 are drawn to a method of treating a subject who has a vascular disorder associated with thrombus formation, the method comprising administering to the subject a therapeutically effective amount of the non-N-glycosylated human annexin A2 comprising SEQ ID NO: 1, wherein the amino acid at position 62 is alanine (A) or glycine (G); and/or the amino acid at position 64 is neither threonine (T) nor Serine (S).
37. The difference between the method recited in claims 10 and 11 of US patent 9314500 B2 and the method recited in instant claims 20, 22, 24, 26 and 27 is that the method recited in claims 10 and 11 of US patent 9314500 B2 does not teach the at least one fibrinolytic recited in instant claim 20; and the limitations of instant claims 22 and 27.
However, in view of the combined teachings of Wang, Anderson et al and Elliott et al as set forth in Section 32 above, it would have been obvious to one of ordinary skilled in the art to modify the method recited in claims 10 and 11 of US patent 9314500 B2 and develop the method recited in instant claims 20, 22, 24, 26 and 27.
Conclusion
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.
No claim is allowed.
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/LI N KOMATSU/Primary Examiner, Art Unit 1658