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 .
Status of the Claims
Claims 1-15 were originally filed December 5, 2023.
The amendment received November 22, 2024 amended claim 1.
The amendment received September 4, 2025 amended claims 1-8.
Claims 1-15 are currently pending.
Claims 1-5 and 8 are currently under consideration.
Election/Restrictions
Applicants’ elected, without traverse, SLLR (SEQ ID NO: 28) and hereditary angioedema as the species in the reply filed on November 22, 2024. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)). Claims 6, 7, and 9-15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on November 22, 2024.
The specification states that SLLR (SEQ ID NO: 28) reads on the functions of claims 3-5.
Claims 6, 9, and 10 are withdrawn because a modification at P1’ was not elected.
Claim 7 is withdrawn because a modification that reduces susceptibility to oxidation was not elected (e.g. P8 in the specification).
Priority
The present application claims status as a DIV of 16/487,858 filed August 22, 2019 (now U.S. Patent 11,851,474) which is a 371 (National Stage) of PCT/EP2018/054490 filed February 23, 2018 which claims foreign priority to EP 17157527.7 filed February 23, 2017.
Please note: the present application is a CON of 16/487,858 filed August 22, 2019 (now U.S. Patent 11,851,474) since the restriction requirement was withdrawn and the method claims were rejoined at the time of allowance.
Please note: applicants agreed that the present application is a CON. See the response received September 4, 2025 (see page 8, first paragraph and page 6, section 3). Also see the ADS submitted September 4, 2025.
Interview
Applicants’ representative provided a “SUMMARY OF INTERVIEW” on September 4, 2025. Below is the examiner of record’s comments regarding the summary.
As discussed in the interview, recovery of breadth of scope may not be possible due to the prior art (see art rejections below). In addition, certain mutations in the RCL were canceled during prosecution in the parent due to the art rejections of record (i.e. only allowable RCL mutations are present in the parent claims which were allowed).
It was agreed during the interview that if the independent claim was modified to recite a full length modified a1 antitrypsin, that the amendment would be examined.
At no point in the interview did the examiner of record state that modified RCLs of SEQ ID NOs: 12-28 in a full length a1 antitrypsin would render the rejections of record moot. See the art rejections below. Furthermore, it is unclear why applicants would cancel SEQ ID NOs: 12, 18, 23-25, and 27 if this were the case (see the claim amendments received September 4, 2025).
At no point in the interview did the examiner of record state that claim 8 would be allowable if the method specified in claim 1 is sufficiently limited to define the modified full length a1 antitrypsin wherein the RCL are defined.
Due to applicants’ representative’s mischaracterization of the interview, no future interviews will be granted and all communication will be in written form and part of the record.
Specification
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
It is unclear why the clean and marked up specifications received September 4, 2025 are labeled “Sequence Listing”.
Withdrawn Objections
The objection to claim 8 regarding “arterial or venous thrombosis” should read “arterial thrombosis, venous thrombosis” so a single conjunction is present in the Markush group (see line 5) is withdrawn in view of the claim amendment received September 4, 2025.
The objection to claim 8 regarding “thrombosis associated with ventricular assist devices or stents” should read “thrombosis associated with ventricular assist devices, thrombosis associated with ventricular stents” so a single conjunction is present in the Markush group (see lines 5-6) is withdrawn in view of the claim amendment received September 4, 2025.
The objection to claim 8 regarding “and” at line 7 should be deleted so only a single conjunction is present in the Markush group is withdrawn in view of the claim amendment received September 4, 2025.
The objection to claim 8 regarding “head trauma or peri-tumor brain edema” should read “head trauma edema, peri-tumor brain edema” so only a single conjunction is present in the Markush group (see line 10) is withdrawn in view of the claim amendment received September 4, 2025.
The objection to claim 8 regarding the space between restenosis and the comma should be deleted (see line 11) is withdrawn in view of the claim amendment received September 4, 2025.
The objection to claim 8 regarding “hypertensive nephropathy and diabetic nephropathy” should read “hypertensive nephropathy, diabetic nephropathy” so that a single conjunction is present in the Markush group (see lines 13-14) is withdrawn in view of the claim amendment received September 4, 2025.
The objection to claim 8 regarding “allergic and respiratory diseases” should read “allergic diseases, respiratory diseases” so that a single conjunction is present in the Markush group (see line 14) is withdrawn in view of the claim amendment received September 4, 2025.
Maintained Objections
Claim 8 is objected to because of the following informalities: the extra common in line 12 should be removed. Appropriate correction is required.
Arguments and Response
Applicants’ argument directed to the objection for claim 8 was considered but are not persuasive for the following reasons.
Applicants contend that the claim was amended accordingly.
Applicants’ arguments are not convincing since no amendment regarding the extra common in line 12 was made.
New Objections Necessitated by Amendment
Claim Objections
Claim 2 is objected to because of the following informalities: “wild-type serpin a1 AT” should read “wild-type a1 antitrypsin” to correlate with the claims (i.e. serpin not utilized, acronym should be defined with the first usage and/or not utilized). Appropriate correction is required.
Claim 3 is objected to because of the following informalities: “unmodified serpin” should read “unmodified a1 antitrypsin” to correlate with the rest of the claims. Appropriate correction is required.
Claim 5 is objected to because of the following informalities: the conjunction should be “and/or” to correlate with “at least one”. Appropriate correction is required.
Withdrawn Rejections
The rejection of claims 1 and 8 on the basis that it contains an improper Markush grouping of alternatives is withdrawn in view of the amendment received September 4, 2025.
The rejection of claims 1 and 8 under 35 U.S.C. 101 as claiming the same invention as that of claims 1 and 6-17 of prior U.S. Patent No. 11,851,474 is withdrawn in view of the amendment received September 4, 2025.
New Rejections Necessitated by Amendment
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.
Claim 1 is 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 "the modified a1 antitrypsin" in line 11. There is insufficient antecedent basis for this limitation in the claim. The following is suggested: "the modified full-length a1 antitrypsin".
Claim 2 is 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. The scope of the presently claimed method is unclear to one of ordinary skill in the art. For example, it is unclear if the limitations of claim 2 alter the functions recited in independent claim 1 (treat a bradykinin-mediated disease, increased inhibition of PK compared to unmodified a1 antitrypsin, more strongly inhibits PK than thrombin or APC). A polypeptide with only 70% identity is expected to have vastly different properties (e.g. 120 amino acid deletions or mutations within a 394mer).
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 3-5 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claims 3 and 4 depend on independent claim 1 and claim 5 depends on claim 4. Independent claim 1 requires a full length a1 antitrypsin with modifications including SEQ ID NO: 28 in the RCL administered to a subject. The specification clearly teaches that SEQ ID NO: 28 has all of the functions of dependent claims 3-5. Therefore, dependent claims 3-5 do not alter the method steps or the reagents utilized in the method and fail to further limit the method. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Maintained and/or Modified* Rejections
*wherein the modification is due to amendment
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 1-5 and 8 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 written description rejection.
Independent claim 1 is drawn to a method for treating a bradykinin-mediated disease comprising administering a modified full length a1 antitrypsin comprising a RCL of SEQ ID NOs: 13-17, 19-22, 26, and 28. The invention as claimed encompasses all known a1 antitrypsin and all potential a1 antitrypsin since there is no limit with regard to the a1 antitrypsin except the RCL of SEQ ID NOs: 13-17, 19-22, 26, and 28. The utilization of “full-length” does not limit the claim to full length with only the RCL mutations (i.e. see dependent claim 2 which only requires 70% identity). In addition, the claim reads on any subject with any disease associated directly or indirectly with bradykinin. The claimed method only required structural information regarding the RCL and not the rest of the a1 antitrypsin. For example, it is unclear how many mutations are encompassed by the claims and how additional mutations might alter the function of the RCL mutations. Present dependent claim 2 only requires 70% identity to wild-type a1 antitrypsin without any indication of how the mutations might alter the RCL or the function of the a1 antitrypsin (i.e. still able to treat a bradykinin-mediated disease?). 70% identity allows for a vast number of mutations and/or deletions (e.g. 120 amino acid difference in a 394mer protein = 69.5% identity). Furthermore, some mutations in a1 antitrypsin actually cause disease, therefore, it is unclear why those mutations would be included in the claims.
The specification does not teach a single in vitro study regarding a bradykinin-mediated disease cell line model, nor does the specification teach a single in vivo animal model for treatment of a bradykinin-mediated disease model much less the myriad of diseases recited in claim 8. Therefore, one skilled in the relevant art would not reasonably conclude that the Applicants had possession of the invention as claimed.
See Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See page 1116.).
Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class wherein the specification provided only the bovine sequence.
Additionally, Cf. University of Rochester v G.D. Searle & Co., Inc., Monsanto Company, Pharmacia Corporation, and Pfizer Inc., No. 03-1304, 2004 WL 260813 (Fed. Cir., Feb. 13, 2004) held that:
Regardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to that subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods.
Arguments and Response
Applicants’ arguments directed to the rejection under 35 USC 112(a) (written description), for claims 1-5 and 8 were considered but are not persuasive for the following reasons.
Applicants contend that utilization of the term “modified full-length a1 antitrypsin” negates the rejection. Applicants contend that the examiner stated that claim 8 would be allowable if the method of claim 1 was sufficiently limited to define the modified full-length a1 antitrypsin wherein the RCP is defined.
Applicants’ arguments are not convincing since the independent claim 1 still reads on any known and unknown “bradykinin-mediated disease” (e.g. directly or indirectly) and any modified full-length a1 antitrypsin without any limit on the number of modifications (e.g. 70% identical – see dependent claim 2; length alone does not limit the number of modifications). In addition, it is unclear if deletions are present in the 70% identical which would negate the full-length limitation.
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 1-5 and 8 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. The scope of the presently claimed method is unclear to one of ordinary skill in the art. For example, it is unclear if the a1 antitrypsin is only modified at the RCL or if additional modifications are present. It is unclear if full-length is altered via other limitations in the claims. See dependent claim 2 wherein only 70% identity is required (e.g. up to 120 amino acids modified and/or deleted in a 394mer which would most likely not be able to treat a bradykinin-mediated disease).
Arguments and Response
Applicants’ arguments directed to the rejection under 35 USC 112(b) (indefinite), for claims 1-5 and 8 were considered but are not persuasive for the following reasons.
Applicants contend that the utilization of “full-length” negates the rejection and the claim allows for additional mutations.
Applicants’ arguments are not convincing since the claim scope regarding the mutations must be clear. Full-length does not alter the number of mutations. In addition, it is unclear if a modified full length a1 antitrypsin with up to 120 amino acids mutated or deleted (i.e. 70% identical; claim 2) would still function as intended and/or how the additional mutations would alter the function of the RCL mutations.
Claim 8 is rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of the myriad of diseases is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: the myriad of diseases have a myriad of causes, symptoms, etc.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Arguments and Response
Applicants’ arguments directed to the rejection regarding improper Markush group for claim 8 were considered but are not persuasive for the following reasons.
Applicants contend that the examiner of record indicated that claim 8 would be allowable if claim 1 is sufficiently limited to define the modified full length a1 antitrypsin.
Applicants’ arguments are not convincing since the examiner of record never indicated allowable subject matter in the interview.
Claim Rejections - 35 USC § 103
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.
Claims 1, 3-5, and 8 are rejected under 35 U.S.C. 103 as being unpatentable over Huntington et al. U.S. Patent Application Publication 2016/0311887 published October 27, 2016 and Bock U.S. Patent Application Publication 2007/0259809 published November 8, 2007.
For present claims 1, 3-5, and 8, Huntington et al. teach methods of administering modified a1 antitrypsin wherein P4 is S, P2 is L, and P1 is R (i.e. SXLR of present SEQ ID NO: 28) to a subject wherein the subject has a disease associated with hemostasis, bleeding, hemorrhage, bleeding disorders, trauma, deficiencies in clotting factors, etc. (please refer to the entire specification particularly the abstract; paragraphs 2, 8-13, 30, 34-40, 44-46, 52, 53, 56-58, 60-63, 67, 144, 151-161, 169, 170, 191, 196-219).
However, Huntington et al. do not teach modification of P3.
For present claims 1, 3-5, and 8, Bock teaches methods of administering modified a1 antitrypsin wherein P3 is L (i.e. residue 2 of present SEQ ID NO: 28) for treatment of bleeding disorders (please refer to the entire specification particularly the abstract; paragraphs 3, 5, 37, 38, 89, 90, 105, 108, 109, 112, 123, 125).
The claims would have been obvious because a particular known technique (i.e. modification of P3 to leucine in the RCL of a1 antitrypsin) was recognized as part of the ordinary capabilities of one skilled in the art. See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007).
Arguments and Response
Applicants’ arguments directed to the rejection under 35 USC 103 as being unpatentable over Huntington et al. and Bock for claims 1-5 and 8 were considered but are not persuasive for the following reasons.
Applicants contend that since Huntington et al. did not test for FXII, kallikrein, or plasmin inhibition that the rejection is moot. Applicants contend that Huntington et al. teaches away from treating bradykinin-mediated disease since Huntington et al. did not test for FXII, kallikrein, or plasmin inhibition. Applicants clearly admit that Bock teaches modified antithrombin where P3 is L and inhibits FXIIa (see paragraphs 5 and 37 of Bock; page 13, last paragraph of the response received September 4, 2025). Applicants then go on the state that Bock does not teach inhibition of FXII (what is FXIIa then?). Applicants state that Bock does not teach inhibition of PK or plasmin. Applicants state that Bock only teaches ATIII and not a1 antitrypsin.
Applicants’ arguments are not convincing since the teachings of Huntington et al. and Bock render the method of the instant claims prima facie obvious.
The present method is a method of administration, not a method of analyzing for FXII, kallikrein, or plasmin inhibition. As long as the same product is administered to the same subject population, the functions would be the same. It is incomprehensible why the attorney of record would expect every laboratory to test for everything.
"Products of identical chemical composition cannot have mutually exclusive properties." See In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.
"The prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." See In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). See also UCB, Inc. v. Actavis Labs, UT, Inc., 65 F.4th 679, 692, 2023 USPQ2d 448 (Fed. Cir. 2023) ("a reference does not teach away if it merely expresses a general preference for an alternative invention but does not criticize, discredit or otherwise discourage investigation into the invention claimed."). See DePuy Spine, Inc. v. Medtronic Sofamor Danek, Inc., 567 F.3d 1314, 1327 (Fed. Cir. 2009)); and Schwendimann v. Neenah, Inc., 82 F.4th 1371, 1381, 2023 USPQ2d 1173 (Fed. Cir. 2023).
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
The present claims only refer to a length and not how many mutations are present. Therefore, each and every amino acid may be mutated (e.g. a1 antitrypsin mutated to ATIII with similar structure and RCL).
The discovery of a mechanism of action is a discovery and not necessarily an invention.
Claims 1-5 and 8 are rejected under 35 U.S.C. 103 as being unpatentable over Huntington et al. U.S. Patent Application Publication 2016/0311887 published October 27, 2016 and Felber et al., 2006, Mutant recombinant serpins as highly specific inhibitors of human kallikrein, FEBS Journal, 273: 2505-2514.
For present claims 1-5 and 8, Huntington et al. teach methods of administering modified a1 antitrypsin wherein P4 is S, P2 is L, and P1 is R (i.e. SXLR of present SEQ ID NO: 28) to a subject wherein the subject has a disease associated with hemostasis, bleeding, hemorrhage, bleeding disorders, trauma, deficiencies in clotting factors, etc. (please refer to the entire specification particularly the abstract; paragraphs 2, 8-13, 30, 34-40, 44-46, 52, 53, 56-58, 60-63, 67, 144, 151-161, 169, 170, 191, 196-219).
However, Huntington et al. do not teach modification of P3.
For present claims 1-5 and 8, Felber et al. teach modified a1 antitrypsin wherein P3 is L (i.e. residue 2 of present SEQ ID NO: 28) and P2 is L and P1 is R (please refer to the entire reference particularly the abstract; Table 1).
The claims would have been obvious because a particular known technique (i.e. modification of P3 to leucine in the RCL of a1 antitrypsin) was recognized as part of the ordinary capabilities of one skilled in the art. See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007).
Arguments and Response
Applicants’ arguments directed to the rejection under 35 USC 103 as being unpatentable over Huntington et al. and Felber et al. for claims 1-5 and 8 were considered but are not persuasive for the following reasons.
Applicants contend that since Huntington et al. did not test for FXII, kallikrein, or plasmin inhibition that the rejection is moot. Applicants contend that Huntington et al. teaches away from treating bradykinin-mediated disease since Huntington et al. did not test for FXII, kallikrein, or plasmin inhibition. Applicants cite Tang et al. All citation must be provided by applicants so that the examiner of record can review the entire citation. Applicants contend that Felber et al. only refer to kallikrein 14.
Applicants’ arguments are not convincing since the teachings of Huntington et al. and Felber et al. render the method of the instant claims prima facie obvious.
The present method is a method of administration, not a method of analyzing for FXII, kallikrein, or plasmin inhibition. As long as the same product is administered to the same subject population, the functions would be the same. It is incomprehensible why the attorney of record would expect every laboratory to test for everything.
"Products of identical chemical composition cannot have mutually exclusive properties." See In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.
"The prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." See In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). See also UCB, Inc. v. Actavis Labs, UT, Inc., 65 F.4th 679, 692, 2023 USPQ2d 448 (Fed. Cir. 2023) ("a reference does not teach away if it merely expresses a general preference for an alternative invention but does not criticize, discredit or otherwise discourage investigation into the invention claimed."). See DePuy Spine, Inc. v. Medtronic Sofamor Danek, Inc., 567 F.3d 1314, 1327 (Fed. Cir. 2009)); and Schwendimann v. Neenah, Inc., 82 F.4th 1371, 1381, 2023 USPQ2d 1173 (Fed. Cir. 2023).
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
The discovery of a mechanism of action is a discovery and not necessarily an invention.
Claims 1, 3-5, and 8 are rejected under 35 U.S.C. 103 as being unpatentable over Huntington et al. U.S. Patent Application Publication 2016/0311887 published October 27, 2016; Bock U.S. Patent Application Publication 2007/0259809 published November 8, 2007; and Kaplan et al., 2010, The plasma bradykinin-forming pathways and its relationship with complement, Molecular Immunology, 47: 2161-2169.
For present claims 1, 3-5, and 8, Huntington et al. teach methods of administering modified a1 antitrypsin wherein P4 is S, P2 is L, and P1 is R (i.e. SXLR of present SEQ ID NO: 28) to a subject wherein the subject has a disease associated with hemostasis, bleeding, hemorrhage, bleeding disorders, trauma, deficiencies in clotting factors, etc. (please refer to the entire specification particularly the abstract; paragraphs 2, 8-13, 30, 34-40, 44-46, 52, 53, 56-58, 60-63, 67, 144, 151-161, 169, 170, 191, 196-219).
However, Huntington et al. do not teach modification of P3.
For present claims 1, 3-5, and 8, Bock teaches methods of administering modified a1 antitrypsin wherein P3 is L (i.e. residue 2 of present SEQ ID NO: 28) for treatment of bleeding disorders (please refer to the entire specification particularly the abstract; paragraphs 3, 5, 37, 38, 89, 90, 105, 108, 109, 112, 123, 125).
For present claims 1, 3-5, and 8, Kaplan et al. teach the importance of clotting factors in angioedema and hereditary angioedema (HAE) (please refer to the entire reference particularly the abstract; Figures 2 and 3; sections 6.2, 6.3).
The claims would have been obvious because a particular known technique (i.e. modification of P3 to leucine in the RCL of a1 antitrypsin; utilizing a1 antitrypsin in diseases associated with clotting factors) was recognized as part of the ordinary capabilities of one skilled in the art. See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007).
Arguments and Response
Applicants’ arguments directed to the rejection under 35 USC 103 as being unpatentable over Huntington et al., Bock, and Kaplan et al. for claims 1-5 and 8 were considered but are not persuasive for the following reasons.
Applicants contend that since Huntington et al. did not test for FXII, kallikrein, or plasmin inhibition that the rejection is moot. Applicants contend that Huntington et al. teaches away from treating bradykinin-mediated disease since Huntington et al. did not test for FXII, kallikrein, or plasmin inhibition. Applicants clearly admit that Bock teaches modified antithrombin where P3 is L and inhibits FXIIa (see paragraphs 5 and 37 of Bock; page 13, last paragraph of the response received September 4, 2025). Applicants then go on the state that Bock does not teach inhibition of FXII (what is FXIIa then?). Applicants state that Bock does not teach inhibition of PK or plasmin. Applicants state that Bock only teaches ATIII and not a1 antitrypsin.
Applicants’ arguments are not convincing since the teachings of Huntington et al., Bock, and Kaplan et al. render the method of the instant claims prima facie obvious.
The present method is a method of administration, not a method of analyzing for FXII, kallikrein, or plasmin inhibition. As long as the same product is administered to the same subject population, the functions would be the same. It is incomprehensible why the attorney of record would expect every laboratory to test for everything.
"Products of identical chemical composition cannot have mutually exclusive properties." See In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.
"The prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." See In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). See also UCB, Inc. v. Actavis Labs, UT, Inc., 65 F.4th 679, 692, 2023 USPQ2d 448 (Fed. Cir. 2023) ("a reference does not teach away if it merely expresses a general preference for an alternative invention but does not criticize, discredit or otherwise discourage investigation into the invention claimed."). See DePuy Spine, Inc. v. Medtronic Sofamor Danek, Inc., 567 F.3d 1314, 1327 (Fed. Cir. 2009)); and Schwendimann v. Neenah, Inc., 82 F.4th 1371, 1381, 2023 USPQ2d 1173 (Fed. Cir. 2023).
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
The present claims only refer to a length and not how many mutations are present. Therefore, each and every amino acid may be mutated (e.g. a1 antitrypsin mutated to ATIII with similar structure and RCL).
The discovery of a mechanism of action is a discovery and not necessarily an invention.
Claims 1-5 and 8 are rejected under 35 U.S.C. 103 as being unpatentable over Huntington et al. U.S. Patent Application Publication 2016/0311887 published October 27, 2016; Felber et al., 2006, Mutant recombinant serpins as highly specific inhibitors of human kallikrein, FEBS Journal, 273: 2505-2514; and Kaplan et al., 2010, The plasma bradykinin-forming pathways and its relationship with complement, Molecular Immunology, 47: 2161-2169.
For present claims 1-5 and 8, Huntington et al. teach methods of administering modified a1 antitrypsin wherein P4 is S, P2 is L, and P1 is R (i.e. SXLR of present SEQ ID NO: 28) to a subject wherein the subject has a disease associated with hemostasis, bleeding, hemorrhage, bleeding disorders, trauma, deficiencies in clotting factors, etc. (please refer to the entire specification particularly the abstract; paragraphs 2, 8-13, 30, 34-40, 44-46, 52, 53, 56-58, 60-63, 67, 144, 151-161, 169, 170, 191, 196-219).
However, Huntington et al. do not teach modification of P3.
For present claims 1-5 and 8, Felber et al. teach modified a1 antitrypsin wherein P3 is L (i.e. residue 2 of present SEQ ID NO: 28) and P2 is L and P1 is R (please refer to the entire reference particularly the abstract; Table 1).
For present claims 1-5 and 8, Kaplan et al. teach the importance of clotting factors in angioedema and hereditary angioedema (HAE) (please refer to the entire reference particularly the abstract; Figures 2 and 3; sections 6.2, 6.3).
The claims would have been obvious because a particular known technique (i.e. modification of P3 to leucine in the RCL of a1 antitrypsin; utilizing a1 antitrypsin in diseases associated with clotting factors) was recognized as part of the ordinary capabilities of one skilled in the art. See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007).
Arguments and Response
Applicants’ arguments directed to the rejection under 35 USC 103 as being unpatentable over Huntington et al., Felber et al., and Kaplan et al. for claims 1-5 and 8 were considered but are not persuasive for the following reasons.
Applicants contend that since Huntington et al. did not test for FXII, kallikrein, or plasmin inhibition that the rejection is moot. Applicants contend that Huntington et al. teaches away from treating bradykinin-mediated disease since Huntington et al. did not test for FXII, kallikrein, or plasmin inhibition. Applicants cite Tang et al. All citation must be provided by applicants so that the examiner of record can review the entire citation. Applicants contend that Felber et al. only refer to kallikrein 14.
Applicants’ arguments are not convincing since the teachings of Huntington et al., Felber et al., and Kaplan et al. render the method of the instant claims prima facie obvious.
The present method is a method of administration, not a method of analyzing for FXII, kallikrein, or plasmin inhibition. As long as the same product is administered to the same subject population, the functions would be the same. It is incomprehensible why the attorney of record would expect every laboratory to test for everything.
"Products of identical chemical composition cannot have mutually exclusive properties." See In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.
"The prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." See In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). See also UCB, Inc. v. Actavis Labs, UT, Inc., 65 F.4th 679, 692, 2023 USPQ2d 448 (Fed. Cir. 2023) ("a reference does not teach away if it merely expresses a general preference for an alternative invention but does not criticize, discredit or otherwise discourage investigation into the invention claimed."). See DePuy Spine, Inc. v. Medtronic Sofamor Danek, Inc., 567 F.3d 1314, 1327 (Fed. Cir. 2009)); and Schwendimann v. Neenah, Inc., 82 F.4th 1371, 1381, 2023 USPQ2d 1173 (Fed. Cir. 2023).
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
The discovery of a mechanism of action is a discovery and not necessarily an invention.
Double Patenting
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 conflicting claims 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); 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 nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) 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 www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 3-5, and 8 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 11,851,474 in view of Huntington et al. U.S. Patent Application Publication 2016/0311887 published October 27, 2016 and Bock U.S. Patent Application Publication 2007/0259809 published November 8, 2007.
U.S. Patent No. 11,851,474 claims a method of treating a bradykinin-mediated disease via administering a modified a1 antitrypsin with a RCL of SEQ ID NOs: 12, 18, 23, 24, 25, and 27 wherein P4 is serine, P3 is leucine, and P1 is arginine and wherein the diseases are the same in present claim 8 and claim 12 of U.S. Patent No. 11,851,474.
For present SEQ ID NO: 28, Huntington et al. teach methods of administering modified a1 antitrypsin wherein P4 is S, P2 is L, and P1 is R (i.e. SXLR of present SEQ ID NO: 28) to a subject wherein the subject has a disease associated with hemostasis, bleeding, hemorrhage, bleeding disorders, trauma, deficiencies in clotting factors, etc. (please refer to the entire specification particularly the abstract; paragraphs 2, 8-13, 30, 34-40, 44-46, 52, 53, 56-58, 60-63, 67, 144, 151-161, 169, 170, 191, 196-219).
Bock teaches methods of administering modified a1 antitrypsin wherein P3 is L (i.e. residue 2 of present SEQ ID NO: 28) for treatment of bleeding disorders (please refer to the entire specification particularly the abstract; paragraphs 3, 5, 37, 38, 89, 90, 105, 108, 109, 112, 123, 125).
The claims would have been obvious because a particular known technique (i.e. modification of P2 to leucine in the RCL of a1 antitrypsin) was recognized as part of the ordinary capabilities of one skilled in the art. See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007).
Arguments and Response
Applicants’ arguments directed to the rejection on the ground of nonstatutory obviousness-type double patenting as being unpatentable over U.S. Patent No. 11,851,474 in view of Huntington et al. and Bock for claims 1, 3-5, and 8 were considered but are not persuasive for the following reasons.
Applicants refer to the arguments for the 35 USC 103 rejection above.
Applicants’ arguments are not convincing since the claimed invention of U.S. Patent No. 11,851,474 in view of Huntington et al. and Bock renders obvious the method of the instant claims. In addition, while a request may be made that objections or requirements as to form not necessary to further consideration of the claims be held in abeyance until allowable subject matter is indicated, the present is a rejection and will not be held in abeyance (see MPEP § 714.02). Please refer to the above arguments regarding the 35 USC 103 rejection.
Claims 1-5 and 8 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 11,851,474 in view of Huntington et al. U.S. Patent Application Publication 2016/0311887 published October 27, 2016 and Felber et al., 2006, Mutant recombinant serpins as highly specific inhibitors of human kallikrein, FEBS Journal, 273: 2505-2514.
U.S. Patent No. 11,851,474 claims a method of treating a bradykinin-mediated disease via administering a modified a1 antitrypsin with a RCL of SEQ ID NOs: 12, 18, 23, 24, 25, and 27 wherein P4 is serine, P3 is leucine, and P1 is arginine and wherein the diseases are the same in present claim 8 and claim 12 of U.S. Patent No. 11,851,474.
For present SEQ ID NO: 28, Huntington et al. teach methods of administering modified a1 antitrypsin wherein P4 is S, P2 is L, and P1 is R (i.e. SXLR of present SEQ ID NO: 28) to a subject wherein the subject has a disease associated with hemostasis, bleeding, hemorrhage, bleeding disorders, trauma, deficiencies in clotting factors, etc. (please refer to the entire specification particularly the abstract; paragraphs 2, 8-13, 30, 34-40, 44-46, 52, 53, 56-58, 60-63, 67, 144, 151-161, 169, 170, 191, 196-219).
Felber et al. teach modified a1 antitrypsin wherein P3 is L (i.e. residue 2 of present SEQ ID NO: 28) and P2 is L and P1 is R (please refer to the entire reference particularly the abstract; Table 1).
The claims would have been obvious because a particular known technique (i.e. modification of P2 to leucine in the RCL of a1 antitrypsin) was recognized as part of the ordinary capabilities of one skilled in the art. See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007).
Arguments and Response
Applicants’ arguments directed to the rejection on the ground of nonstatutory obviousness-type double patenting as being unpatentable over U.S. Patent No. 11,851,474 in view of Huntington et al. and Felber et al. for claims 1, 3-5, and 8 were considered but are not persuasive for the following reasons.
Applicants refer to the arguments for the 35 USC 103 rejection above.
Applicants’ arguments are not convincing since the claimed invention of U.S. Patent No. 11,851,474 in view of Huntington et al. and Felber et al. renders obvious the method of the instant claims. In addition, while a request may be made that objections or requirements as to form not necessary to further consideration of the claims be held in abeyance until allowable subject matter is indicated, the present is a rejection and will not be held in abeyance (see MPEP § 714.02). Please refer to the above arguments regarding the 35 USC 103 rejection.
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 statuto