Detailed Actions
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 10 October 2025 has been entered.
Status of the Claims
Claims 1-50 were originally filed October 1st, 2021. The preliminary amendment filed February
18th, 2022 has been entered. A request for continued examination was filed 10 October 2025 with newly added claims 64 and 65. Currently, claims 51, 52, 59, 60 and 63-65 are currently pending and under consideration.
Withdrawn Rejections
In view of Applicant amending claim 51 to recite “a value” before “the value” the 35 USC 112(b) rejection of claim 51 regarding this ambiguity is hereby withdrawn.
In view of Applicant amending claim 52 to specify the percentage if from total HMWK the 35 USC 112(b) rejection of said claim is hereby withdrawn.
In view of Applicant cancelling claim 56 the 35 USC 112(d) rejection over said claim is hereby withdrawn.
Upon further consideration the 35 USC 103 rejection of claims 51, 52, 59, 60, and 63 over Coleman, Scott, and Bernstein and Moellman is hereby withdrawn.
Upon further consideration, regarding the recitation of the functional properties “wherein the detection agent specifically binds cleaved HMWK as compared to intact HMWK (see claim 51 lines 12-13) and “wherein the detection agent is an antibody that binds to the C-terminus of the light chain of cleaved HMWK” (see claim 51 lines 14-15) the pending claim interpretation and all non-statutory double patenting rejections are hereby withdrawn.
Claim Objections
Claim 59 is objected to because of the following informalities:
Claim 59 recites, “the levels of the cleaved HMWK are measured” in lines 1-2 and should recite, “the level[[s]] of the cleaved HMWK [[are]]is measured”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
New Matter
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 51, 52, 59, 60, and 63-65 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.
The claims are drawn to a method for identifying a disorder as being associated with elevated contact system activation and administering an effective amount of a plasma kallikrein (pKal) inhibitor to the subject identified as having the disorder (see claim 51 lines 1-3). The specification does not disclose or contemplate a method for identifying a disorder as being associated with elevated contact system activation and administering a pKal inhibitor. The specification is drawn to methods for i. identifying a subject at risk for or having a pKal-mediated disorder, ii. determining if a disorder is susceptible to treatment with a pKal inhibitor, iii. for evaluating a treatment of a pKal-mediated disorder in a subject, iv. determining a value of cleaved kininogen, a value of intact kininogen, or both, in a sample, v. treating a pKal-mediated disease, and vi. evaluating a subject (see specification pg. 2, 2nd full para, pg. 3, 3rd full para, pg. 4, 2nd and last para, pg. 5, 2nd and 3rd para). Therefore, reciting a method for identifying a disorder as being associated with elevated contact system activation and administering an effective amount of a pKal inhibitor to the subject identified as having the disorder is new matter that reaches beyond the specification as originally filed because the specification never contemplated the particular subgenus of methods encompassed by the claim language.
Applicant's arguments filed 31 March 2025 (referred to herein as Remarks 1) have been fully considered but they are not persuasive.
Applicant argues the instant specification describes the instantly claimed method and points to particular locations in the specifications (see Remarks 1 pg. 5, 2nd para).
Applicant points to the following places in the specification for support for the instantly claimed method:
Figure 1 this describes the contact system in general.
Specification page 27 is drawn to the “a value (e.g., percentage) of cleaved HMWK, intact HMWK, or both, can be used as a biomarker for identifying subjects having or at risk for such diseases, for identifying a disorder that is likely to be susceptible to treatment with a pKal inhibitor, and for evaluating the effectiveness of a disease treatment involving one or more pKal inhibitors”. In particular, identifying a disorder that is likely to be susceptible to treatment with a pKal inhibitor is drawn to a particular subpopulation of disorders that are sensitive to pKal inhibition (see specification pg. 3, 3rd para). The current claim is more broadly a method of identifying a disorder associated with elevated contact system activation using a single sample from a single subject and then treating the subject using a pKal inhibitor. The instantly claimed method is therefore drawn to identifying any disorder with elevated contact system activation and administering a pKal inhibitor regardless of the inhibitor’s efficacy.
Example 1 provides support for an antibody (i.e., close 11H05) can effectively detect cleaved kininogen in human plasma samples (see specification pg. 53, 3rd para).
Example 3 provides support for detecting differences in HMWK in patients with HAE. While the specification does disclose, “Using this latter approach, the assay could be used to screen samples from different diseases and identify diseases associated with contact system activation” (see specification sentence spanning pgs. 56-57). This is the only support in the specification for identifying diseases associated with contact system activation. However, it is noted this statement is in reference to an assay with specific parameters, specifically, using the percent of 2-chain signal in plasma samples suspected of involving contact activation and compared to that of plasma from normal healthy individuals (see specification pg. 56 last para). The instant claim is broader in reciting “a subjecting having or suspected of having a disorder”, “a control value”, “determining a value of cleaved HMWK”, and does not support treating said identified disorder with any pKal inhibitor. The disclosure at best is drawn to screening samples.
Example 7 is drawn to detecting elevated levels of contact system activation in HAE, UC, RA, and CD. However, it was known in the art at the time of filing that HAE, US, RA and CD exhibited increased levels of contact activation (see Stadnicki et al. as cited on the IDS received 03/31/2025, pg. 2356 sentences spanning cols 1-2; see Colman, Robert (1999) Plasma and tissue kallikrein in arthritis and inflammatory bowel disease. Immunopharmacology. Vol. 43, Iss. 2-3, pgs. 103-108, in particular pg. 104, 2nd col. 2nd para; see Riedl et al. as cited on the IDS received 10/10/2025, pg. S34, 2nd col).
While each element is disclosed in the specification these elements are individually drawn to different methods (i.e., identifying a subject at risk, determining if a disorder is susceptible to treatment with a pKal inhibitor, evaluating treatment, treating a pKal mediated diseases, determining the value of cleaved kininogen, and evaluating a subject) the elements as a whole are not directed to a method of identifying diseases associated with contact system activation and administering an effective amount of a pKal inhibitor to the subject identified as having the disorder. The particular recitation of identifying diseases associated with contact system activation is a suggested use of a particular assay for screening purposes and is not described in general terms nor with the breadth of the current claim language. Therefore, reciting a method for identifying a disorder as being associated with elevated contact system activation and administering an effective amount of a pKal inhibitor to the subject identified as having the disorder is new matter that reaches beyond the specification as originally filed because the specification never contemplated the particular subgenus of methods encompassed by the claim language.
Written Description
Claim 51, 52, 59, 60, and 63-65 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.
Claim 51 is drawn to “wherein the detection agent specifically binds cleaved HMWK as compared to intact HMWK” (see lines 12-13). The specification defines “specifically binds” as reacting or associating more frequently, more rapidly, with greater duration and/or with grater affinity with a particular target antigen than it does with alternative targets (see specification pg. 28 last para). In addition, the term does not necessarily require (although it can include) exclusive binding (see specification pg. 29, 1st para). Therefore, the language of claim 51 encompasses a genus of antibodies with any degree of increase in binding frequency, rate of association, length of binding, or strength of binding to cleaved HMWK compared to intact HMWK. Furthermore, claim 51 is drawn to a second function, i.e., antibodies that also bind the C-terminus of the light chain of cleaved HMWK (see claim 51 lines 14-15). It is noted the specification teaches the C-terminus of cleaved HMWK is identical to intact HMWK (see figure 4).
Applicants have disclosed murine anti-HMWK (11H05) antibody has a “higher sensitivity” to intact HMWK under reducing conditions as compared to cleaved HMWK (see specification pg. 56 last para, figure 5A and B). Therefore, Applicants have not disclosed a single antibody that preferentially binds cleaved HMWK as compared to intact HMWK as instantly claimed. Applicant also discloses intact HMWK is a single polypeptide whereas cleaved HMWK is a 2 chain structure comprising a heavy and light chain linked via a disulfide bond (see specification figure 4). Furthermore bradykinin a vasodilator is cleaved from intact HMWK (see specification 1, last para). The ordinary artisan would understand there are structural differences between intact and cleaved HMWK which would contribute to the unpredictability of making antibodies that exhibit a preference for cleaved HMWK.
Antibodies with the instantly claimed preferential binding are not known in the art. The closest antibody with the instantly claimed functions is a post filing patent (i.e., 2016) which discloses anti-HMWK antibody 559B-M0004-B04. The antibody binds preferentially to cleaved HMWK and not intact HMWK; however, the ‘747 patent also teaches the antibody specifically binds to the N-terminally located domain 5 (see ‘747 patent col. 47 Table 2, lines 36-37). While other anti-HMWK antibodies are disclosed the ‘747 patent, the patent is silent as to the claimed preferential binding (e.g., rate of association, length of binding) to cleaved HMWK as compared to intact HMWK. Thus, there are no known antibodies with the instantly claimed functional properties. Therefore, the instant specification “claims merely recite a description of the problem to be solved while claimed all solutions to it and… cover any compound later actually invented and determined to fall within the claim’s functional boundaries— leaving it to the pharmaceutical industry to complete an unfinished invention.” Ariad Pharmaceuticals, Inc. v. Eli Lilly and Co., 598 F.3d 1336, 1353 (Fed. Cir. 2010).
Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function … does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”). Furthermore, Applicant has not disclosed a representative number of species of the claimed genus.
In conclusion, Applicant has not described the claimed invention sufficiently to show they had possession of the claimed genus of anti-HMWK antibodies that preferentially binds cleaved HMWK and also bind to the C-terminus of the light chain of cleaved HMWK in terms of binding frequency, rate of association, length of binding, or strength of binding.
Claim Rejections - 35 USC § 112(b)
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 51, 52, 59, 60, and 63-65 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 51 recites the limitation "the subject" in line 3. There is insufficient antecedent basis for this limitation in the claim.
Claim 51 is drawn to a method of identifying a disorder as being associated with elevated contact system activation the method comprising measuring a pKal marker in a sample from a subject having or suspected of having a disorder associated with elevated contact system activation, determining a value of cleaved HMWK; identifying the disorder as being associated with elevated contact system activation; wherein the disorder associated with elevated contact system activation is UC, RA, CD, or cirrhosis.
First, it is unclear which “a disorder” the wherein clause identifying the disorders is associated with (i.e., preamble and/or subject) as there are multiple recitations of “a disorder” followed by recitation of “the disorder” (see lines 1 and 5).
Second, the scope of the claim is unclear. The preamble is drawn to both i. identifying a disorder as being associated with elevated contact system activation and ii. administering an effective amount of a pKal inhibitor to the subject identified as having the disorder. It is unclear the claim is drawn to identifying a disorder generally, for example, identifying UC as being associated with elevated contact system activation, and then treating subjects having or suspected of having UC. Alternatively, is claim 51 drawn to diagnosing a disorder as being associated with elevated contact system activation and treating the same subject with a pKal inhibitor.
Third, the language of claim 51 encompasses subjects having the disorder the method is drawn to identifying. Thus, the scope of the identification is unclear. Is the claim drawn to identifying a subject of subjects with the claimed disorders who also have elevated levels of contact system activation or alternatively is the claim drawn to confirming the diagnosis of a claimed disorder.
Applicant's arguments filed 10 October 2025 (referred to herein as Remarks2) have been fully considered but they are not persuasive.
Applicant argues claim 51 has been amended to clarify the disorders associated with elevated contact system activation are UC, RA, CD, and cirrhosis (see Remarks pg. 5, 1st full para). However, it is unclear if the instantly claimed disorders are associated with the clause in the preamble and/or the clause regarding the particular subject. Therefore, for the reasons stated above the 35 USC 112(b) rejection of claims 51, 52, 59, 60, and 63-65 is hereby maintained.
The following 35 USC 112(b) rejections are new grounds for rejections.
Claims 51, 52, 59, 60, and 63-65 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 51 is drawn to “wherein the detection agent is an antibody that binds to the C-terminus of the light chain of cleaved HMWK” (see claim 51 lines 14-15). It is unclear what is considered the C-terminal region. For example, is an antibody that binds to any location in domain 6 within the scope of or is an antibody that bind only a portion of domain 6 within the scope of the “C-terminus of the light chain”. In addition, the specification teaches cleaved and intact HMWK have identical structure, i.e., domain 6, therefore it is unclear how an antibody can preferentially bind the C-terminus of cleaved HMWK as compared to intact HMWK when they have identical structure.
Claims 52 and 59 recites the limitation "the level" in line 1. There is insufficient antecedent basis for this limitation in the claim.
Claim 64 is drawn to wherein the method further comprises separating cleaved HMWK and intact HMWK by electrophoresis. It is clear when this step is performed. For example, is this step part of the identification of the disorder or alternatively performed after the last step recited in claim 51 (i.e., after administration of the pKal inhibitor).
Claim 65 recites the limitation "the reference value" in line 1. There is insufficient antecedent basis for this limitation in the claim.
Conclusion
No claim allowed.
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/H.A.P./ Examiner, Art Unit 1644
/AMY E JUEDES/ Primary Examiner, Art Unit 1644