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 .
Response to Amendment
Applicant’s remarks and amendments to the claims received 02/20/2026 have been acknowledged. Claims 18, 19, and 22 have been amended. Claims 26-44 are newly added. The claim amendments overcome the 35 USC 112(d) rejection over claim 22 previously set forth.
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 18, 19, 22, 26, 27, 28, 29, 32, 33, 34, 35, 36, 37, 38, 39, 40, and 41 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 18 fails to recite any structural features shared by members of the genus DPP3 inhibitory antibodies correlated with the function of blocking DPP3 activity and treating shock in a subject, wherein the antibodies are defined only heavy and light chain CDR3s.
Claim 22 fails to the genus of anti-ADM antibodies or fragments thereof defined only by heavy and light chain CDR3s having the functional property of inhibiting ADM activity and treating shock in a subject.
The guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, § 1 "Written Description" Requirement make clear that if a claimed genus does not show actual reduction to practice for a representative number of species, then the Requirement may be alternatively met by reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the genus (MPEP 2163).
In The Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412) 19 F. 3d 1559, the court held that disclosure of a single member of a genus (rat insulin) did not provide adequate written support for the claimed genus (all mammalian insulins). In this same case, the court also noted:
“A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. See Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen). It is only a definition of a useful result rather than a definition of what achieves that result. Many such genes may achieve that result. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin [e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate."). Accordingly, naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.”
The court has further stated that “Adequate written description requires a precise definition, such as by structure, formula, chemical name or physical properties, not a mere wish or plan for obtaining the claimed chemical invention.” Id. at 1566, 43 USPQ2d at 1404 (quoting at 1171, 25 USPQ2d at 1606). Also see (CAFC 2002). Enzo-Biochem v. Gen-Probe Fiers, 984 F.2d 01-1230.
Claim 18 is broadly drawn to a method of treating refractory shock in a subject comprising administering an inhibitor of DPP3 activity to the subject, wherein the inhibitor of DPP3 activity is an antibody or antibody fragment comprising six CDRs all of which are undefined with the exception of HCDR3 and LCDR3.
In order to bind antigen, a conventional antibody or antigen-binding fragment must have six complementarity defining regions (CDRs) (Janeway, see selection, in particular section 3-6). As presently written, claim 18 does not disclose the amino acid sequences of all six non-degenerate CDRs for the genus of antibodies or antibody fragments having the functional property of blocking DPP3 activity in order to treat refractory shock in a subject. The CDR3 sequences from the heavy and light chains alone are not sufficient to define antibody binding to a specific target and functional outcome. For example, the same HCDR3 can be generated from different V(D)J rearrangements, but target binding depends on the specific VH/VL context and pairing; thus HCDR3 alone is insufficient for defining antibody specificity. Notably, in unselected libraries, most antibodies sharing an identical HCDR3 fail to bind the target (CDK2), highlighting the importance of the surrounding sequence and structural context (D’Angelo et al, Abstract and Page 8, right column). Without further guidance, artisans would necessarily have to engage in additional research (e.g. screening and testing) to identify the full scope of inhibitors that block DPP3 activity and treat shock in a subject. Therefore, defining the CDR3 regions alone of an inhibitory DPP3 antibody is insufficient, and all six CDR sequences having the functional properties set forth in the claims must also be identified.
Similarly, claim 22 (which depends on claim 19) recites that administration of an anti-ADM antibody or antibody fragment. In order to bind antigen, a conventional antibody or antigen-binding fragment must have six complementarity defining regions (CDRs) (Janeway, see selection, in particular section 3-6). As presently written, claim 22 does not disclose the amino acid sequences of six non-degenerate CDRs for the genus of anti-ADM antibodies or antibody fragments having the functional property of treating shock in a subject. As stated earlier, not all antibodies exert the same biological effect, as variation can occur depending on the specific epitope bound.
Therefore, the claimed genera of DPP3 inhibitory antibodies and anti-ADM antibodies lacks adequate written description because there does not appear to be any correlation between the structure of each antibody and the function of binding and/or blocking the activity of their respective targets. Thus, one of ordinary skill in the art would reasonably conclude that the applicant was not in possession of the full breadth of the claimed genera of DPP3 inhibitory antibodies and anti-ADM antibodies at the time the instant application was filed.
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 22 and 36-42 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 22, as amended, recites that treatment with an anti-ADM antibody is initiated when pro-ADM levels are above a predetermined threshold. Alternatively, the initiated treatment is withheld and/or terminated if the pro-ADM levels are below a predetermined threshold. As presently written, step 1 of the method is measuring pro-ADM levels. Step 2 is either a) initiating treatment when pro-ADM levels are above a threshold OR b) terminating the initiated treatment when pro-ADM levels are below a threshold. The only recited measurement of pro-ADM levels occurs prior to treatment initiation. The alternative limitation requires an already initiated treatment to be terminated based on biomarker levels below a threshold. However, no subsequent measuring step after initiating treatment is recited to provide a basis for withholding or terminating treatment later. Therefore, claim 22 does not clearly set forth the metes and bounds of the patent prosecution desired. Claims 36-42, which depend directly or indirectly from claim 22, do not cure the deficiencies of claim 22 and are thus also rejected.
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.
Claim 19 is 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.
Claim 19 recites several angiotensin receptor agonists and/or precursors thereof including angiotensin II, III, IV, and analogues thereof; however, claim 32 (which depends on claim 19) recites that the angiotensin receptor agonist and/or precursor is angiotensin I. Therefore, claim 32 improperly broadens the scope of claim 19.
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.
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 18, 26-31, and 44 are rejected under 35 U.S.C. 103 as being unpatentable over Bergmann (WO2017182561A1, of record) in view of Jentzer et al (Jentzer, Jacob C., et al. "Management of refractory vasodilatory shock." Chest 154.2 (2018): 416-426), hereinafter Jentzer, and Kaufmann et al (Kaufmann, Paul, et al. "A novel and highly efficient purification procedure for native human dipeptidyl peptidase 3 from human blood cell lysate." PLoS One 14.8 (2019): e0220866), hereinafter Kaufmann.
Bergmann discloses a method for treating a disease or condition associated with necrotic processes in a subject comprising administering an inhibitor of DPP3 activity to the subject, wherein the subject has an elevated level of DPP3 above a predetermined threshold level (Page 39, Ln. 13-15; Page 40, Ln. 22-25). While it is not explicitly stated that cardiogenic or septic shock are diseases/conditions accompanied by or related to necrotic processes, elevated DPP3 levels relative to a predetermined threshold is a diagnostic criterion for said diseases or conditions. Specifically, it has been shown that patients with cardiogenic or septic shock exhibit elevated DPP3 plasma levels compared to healthy controls (Example 1). Thus, elevated DPP3 levels relative to a predetermined threshold can be used to identify a subject with shock states (e.g. cardiogenic or septic shock) that can be treated with a DPP3 activity inhibitor. The DPP3 activity inhibitor is, in some embodiments, an anti-DPP3 antibody or fragment thereof (Page, 36, Ln. 4-18). The threshold is predetermined by measuring DPP3 concentration and/or DPP3 activity in healthy controls and calculating, e.g., the 75th percentile, 90th percentile, or 95th percentile, wherein the upper border of a percentile defines the threshold for healthy versus diseased patients. In relation to said percentiles, the threshold that divides between healthy and diseased patients may be between 5 and 25 ng/ ml in plasma using a sandwich type anti-DPP3 immunoassay (Page 23, Ln. 4-16). It is further stated that a person skilled in the art knows a) how to determine thresholds from conducted previous studies and b) that a specific threshold value may depend on the cohort used for calculating a pre-determined threshold that can be later-on used in routine (Page 23, Ln. 18-24). Thus, the threshold value for DPP3 levels is recognized in the prior art as a result-effective variable to determine healthy vs diseased populations.
Bergmann does not teach that the subject has refractory shock nor the anti-DPP3 antibody having the CDR or variable sequences recited in the instant claims.
However, Jentzer teaches that refractory shock is a lethal manifestation of cardiovascular failure defined by an inadequate hemodynamic response to high doses of vasopressor medications. Approximately 7% of critically ill patients will develop refractory shock, with short-term mortality exceeding 50% (Abstract), thus patients with refractory shock represent a patient population in need of therapeutic intervention.
Kaufmann teaches the anti-DPP3 monoclonal antibody AK1967 (see “Protein purity analysis and Western Blotting” section on Page 3). Per the instant specification, clone AK1967 comprises the heavy and light chain pair of SEQ ID NOs: 11 and 12, respectively. The heavy chain of SEQ ID NO: 11 fully comprises the VH chain of SEQ ID NO: 4 and the CDRs of SEQ ID NOs: 6-8. The light chain of SEQ ID NO: 12 fully comprises the VL chain of SEQ ID NO: 5 and the CDRs of SEQ ID NO: 9, KVS, and SEQ ID NO: 10 (see “Examples of Sequences” on Pages 89-90 of the instant specification). As such, the AK1967 antibody disclosed by Kaufmann comprises the CDR and variable sequences of the inhibitor of DPP3 activity recited in the instant claims. Further, per the PLOS Journal guidelines on the availability of materials (see attached ASM Journals Availability of Data and Materials), authors are expected “make all relevant materials that may be reasonably requested by others available without restriction upon publication of the work” (see Materials, Software and Code Sharing for PLOS Journals, OA.Appendix). Thus, the AK1967 clone was otherwise available to the public. Per the instant claims, the minimal structure required for an antibody to inhibit DPP3 activity is an HCDR3 of SEQ ID NO: 8 and a LCDR3 of SEQ ID NO: 10. Since the clone AK1967 has the same CDRs, variable domains, and heavy and light chains set forth in the claims, then said clone can be used to inhibit DPP3 activity.
It would have been obvious to one of ordinary skill in the art to modify the method of treating a disease or condition associated with necrotic processes (e.g. cardiogenic or septic shock) disclosed by Bergmann such that the patient has refractory cardiogenic shock and the DPP3 inhibitory antibody used for treatment is the clone AK1967. One of ordinary skill in the art would have been motivated to do so since refractory shock is a lethal manifestation of cardiovascular failure defined by an inadequate hemodynamic response to high doses of vasopressor medications with short-term mortality exceeding 50% as taught by Jentzer and thus patients with refractory shock represent a subset of shock patients in need of therapeutic intervention whereas Bergman teaches that administration of an annti-DPP3 antibody can be used to treat different types of shock. As such, administration of anti-DPP3 antibody would likewise be beneficial in the subset of patients having refractory shock. Further, the courts have held that [W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955), thus it would have been prima facie obvious to one of ordinary skill in the art to determine by routine experimentation the optimum threshold values of DPP3 levels to arrive at the specific embodiments recited in the claims for identifying and treating patients having refractory shock. Lastly, it would have been obvious to artisans to substitute anti-DPP3 antibody of Bergmann with the clone AK1967 disclosed by Kaufmann since they have the same structure and thus can be used for the same purpose. An express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213USPQ 532 (CCPA 1982). Therefore one of ordinary skill in the art would reasonably expect that administration of the anti-DPP3 antibody AK1967 to be therapeutically beneficial in the treatment of patients with refractory shock identified as having DPP3 levels above a predetermined threshold.
Claims 19 and 32-35 are rejected under 35 U.S.C. 103 as being unpatentable over Bergmann in view of Jentzer, and Kauffman, as applied to claim 18, 26-31, and 44 above, and further in view of Chawla (US20170196931A1).
The teachings of Bergmann in view of Jentzer and Kauffmann have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the DPP3 inhibitor is administered in combination with an angiotensin receptor agonist recited in the claims including angiotensin I, II, III, IV and analogues thereof.
However, Chawla teaches that angiotensinogen, Angiotensin I, Angiotensin II, angiotensin III, and angiotensin IV are hormones naturally produced by the body that regulate blood pressure via vasoconstriction and sodium reabsorption (Para. 0005) and thus discloses methods of treating hypotension (such as catecholamine-resistant hypertension) in a patient comprising administering an angiotensin therapeutic agent such as angiotensin I, angiotensin II, angiotensin III, angiotensin IV, or analogues thereof (Para. 0006-0007), wherein the patient has cardiogenic, distributive, or septic shock (Para. 0047). The angiotensin II is preferably 5-L-isoleucine angiotensin II (or human angiotensin II) having the sequence set forth in SEQ ID NO: (DRVYIHPF) corresponding to SEQ ID NO: 13 (DRVYIHPF) (Para. 0039 and 0068). Angiotensin II analogues contemplated for use include 5-L-valine angiotensin II [SEQ ID NO: 2, DRVYVHPF)] corresponding to SEQ ID NO: 14 (DRVYVHPF) of the instant claims; [Asn1-Phe4-]-angiotensin II [SEQ ID NO: 3 (NRVFIHPF)] corresponding to SEQ ID NO: 15 (NRVFIHPF) of the instant claims; angiotensin II nonapeptide [SEQ ID NO: 4 (NRVYYVHPF)] corresponding to SEQ ID NO: 17 (NRVYYVHPF) of the instant claims; [Asn1-Ile5-Ile8]-angiotensin II [SEQ ID NO:5 (NRVYIHPI)] corresponding to SEQ ID NO: SEQ ID NO: 18 (NRVYIHPI) of the instant claims; [Asn1-Ile5-Ala8]-angiotensin II [SEQ ID NO:6 (NRVYIHPA)] corresponding to SEQ ID NO: 19 (NRVYIHPA) of the instant claims; and [Asn1-diiodoTyr4-Ile5]-angiotensin II [SEQ ID NO:7 (NRVYIHPF)] corresponding to SEQ ID NO: 20 (NRVYIHPF) of the instant claims (Para. 0039 and 0068). The angiotensin III preferably has the sequence set forth in SEQ ID NO: 8 (or human angiotensin III) (RVYIHPF) corresponding to SEQ ID NO: (RVYIHPF) of the instant claims. The angiotensin III analogues also contemplated for use include 4-valine angiotensin III [SEQ ID NO: 9 (RVYVHPF)] corresponding to SEQ ID NO: 22 (RVYVHPF) of the instant claims; [Phe3]-angiotensin III [SEQ ID NO:10 (RVFIHPF)] corresponding to SEQ ID NO: 23 of the instant claims; [Ile4-Ala7]-angiotensin III [SEQ ID NO:11 (RVYIHPA) corresponding to SEQ ID NO: 24 of the instant claims (RVYIHPA); and [diiodoTyr3-Ile4]-angiotensin III [SEQ ID NO:12 (RVYIHPF)] corresponding to SEQ ID NO: 25 of the instant claims (Para. 0040 and Para. 0070). The angiotensin IV preferably has the sequence set forth in SEQ ID NO: 13 (or human angiotensin IV) (VYIHPF) corresponding to both SEQ ID NO: 16 (angiotensin II hexapeptide - VYIHPF) and SEQ ID NO: 26 (VYIHPF) of the instant claims. The angiotensin IV analogues contemplated for use include Val3 -angiotensin IV [SEQ ID NO: 14 (VYVHPF)] corresponding to SEQ ID NO: 27 (VYVHPF) of the instant claims; [Phe2]-angiotensin IV [SEQ ID NO:15 (VFIHPF)] corresponding to SEQ ID NO: 28 (VFIHPF) of the instant claims; [Ile3-Ala6]-angiotensin IV [SEQ ID NO:16 (VYIHPA)] corresponding to SEQ ID NO: 29 (VYIHPA) of the instant claims; and [diiodoTyr2-Ile3]-angiotensin IV [SEQ ID NO:17 (VYIHPF)] corresponding to SEQ ID NO: 30 (VYIHPF) of the instant claims (Para. 0041 and Para. 0072) (see also Examples of Sequences on Pages 91-92 of the instant specification).
It would have been obvious to one of ordinary skill in the art to administer an angiotensin receptor agonist such as angiotensin I, II, III, IV, or an analogue thereof in combination with an inhibitor of DPP3 activity to a subject having an elevated DPP3 level relative to a predetermined threshold, a characteristic of necrotic-related processes such as cardiogenic and septic shock. One of ordinary skill in the art would have been motivated to do so since angiotensin I, II, III, IV and analogues thereof regulate blood pressure via vasoconstriction and sodium reabsorption and thus can be used to effectively treat hypotension in patients suffering from various forms of shock (e.g. cardiogenic, distributive, or septic shock) in patients, including hypotension that is resistant (or refractory) to other treatment modalities (e.g. catecholamines) as taught by Chawla. Therefore, one of ordinary skill in the art would reasonably expect that administering angiotensin I, II, III, IV or an analogue thereof angiotensin II in combination with an DPP3 activity inhibitor to effectively treat a shock in a subject having elevated DPP3 levels relative to a predetermined threshold.
Claims 22 and 36-43 are rejected under 35 U.S.C. 103 as being unpatentable over Bergmann in view of Jentzer, Kauffmann, and Chawla, as applied to claims 18, 19, 18, 26-35, and 44 above, and further in view of Xu et al (Xu, Tu, et al. "Flexible combination of multiple diagnostic biomarkers to improve diagnostic accuracy." BMC medical research methodology 15.1 (2015): 94, of record), hereinafter Xu, Morgenthaler et al (EP1619505B1, of record), hereinafter Morgenthaler, and Struck et al (WO2019077082A1), hereinafter Struck.
The teachings of Bergmann in view of Jentzer, Kauffmann, and Chawla have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the level of pro-adrenomedullin or fragments thereof in a sample of plasma is also determined and treatment with an anti-ADM antibody or fragment thereof is initiated when the level is above a predetermined threshold or treatment with the anti-ADM antibody is withheld/terminated if the determined level of pro-adrenomedullin or fragments thereof is below said predetermined threshold, wherein the anti-ADM antibody has the CDRs recited in the instant claims and the predetermined threshold level of pro-ADM comprises ADM-NH2 in a range of 50 pg/ml – 250 pg/mL/ MR-proADM in a range of 0.5 nmol/L and 3 nmol/L; or CT-proADM in a range of 85 pmol/L – 500 pmol/L.
However, Xu teaches that diagnosis based on multiple biomarkers assessed in an individual rather a single biomarker improves diagnostic accuracy (Abstract and 3rd paragraph under Introduction).
Morgenthaler further teaches determining the concentration of pro-adrenomedullin (pro-ADM) or physiologically occurring fragments thereof in a body fluid sample from a critically ill patient to identify a life-threatening crisis requiring intervention, including shock states such as septic shock, and to assess mortality risk for these disease states (Abstract, Para. 0002, 0003, 0025, and 0028–0031). Further disclosed are specific cut-off values for interpreting such measurements in septic ICU patients where values above 8 nmol/L identify patients that have greatly increased mortality risk (para. 0042–0044). When pro-ADM levels are critically high, therapeutic intervention is warranted via administration of adrenomedullin antagonists such as antibodies that bind ADM and block its receptor interaction (e.g. antibodies to adrenomedullin that block its receptor binding sites: “immunological neutralization”) to treat conditions such as shock (para. 0055–0057, 0060, and 0066). Accordingly, Morgenthaler describes measuring pro-ADM in shock patients, comparing the level to a disclosed threshold, and initiating treatment with an anti-ADM antibody when the level exceeds that threshold.
Struck further teaches the anti-ADM antibody HAM8101 (adrecizumab) for use in treating subjects suffering from shock (e.g. sepsis/septic shock), wherein HAM8101 comprises the heavy chain of SEQ ID NO: 26 and the light chain of SEQ ID NO: 27 (Page 6, Ln. 26-31 to Page 7, Ln. 1-2; Page 7, Ln. 13-15; Page 19, Ln. 4-6; Page 13, Ln. 15-32; Example 1, Page 44). The heavy chain of adrecizumab fully comprises the CDRs of SEQ ID NOs: 38-40 and the VH chain of SEQ ID NO: 44 recited in the instant claims. The light chain of adrecizumab fully comprises the CDRs of SEQ ID NO: 41, RVS, SEQ ID NO: 42 of the instant claims. HAM8101 is identified as adrecizumab and thus has all of the sequences recited in the instant claims (see “Examples of Seqeunces on Page 94 of instant specification). Further disclosed is the determination of specific proADM-derived biomarkers including MR-proADM and CT-proADM (Page 6). Elevated levels of these pro-ADM fragments above a certain threshold are described as correlating with enhanced risk of adverse outcome (Page 28, Ln. 4-11). For plasma MR-proADM, the threshold is between 0.5 to 1.5 nmol/L, preferably 0.7 to 1 nmol/L, and most preferably is 0.8 nmol/L (Page 27, Ln. 1-3). For plasma CT-proADM, the threshold is between 85 to 350 pmol/L, preferably between 100 to 200 pmol/L, and most preferably is 150 pmol/L (Page 27, Ln. 5-7). Additionally, healthy-subject reference values for plasma mature ADM-NH2 (or bio-ADM) levels are also taught, including a median value of about 24.7 pg/mL, a lowest value of about 11 pg/ml and a 99th percentile value at about 43 pg/ml (Page 30, Ln. 25-29). These disclosed reference values can thus be used to distinguish healthy subjects from subjects having elevated ADM-NH2 levels associated with disease and/or shock states via routine optimization. MR-proADM has the amino acid sequence of SEQ ID NO: 4 (ELRMSS SYPTGLADVK AGPAQTLIRP QDMKGASRSP EDSSPDAARI RV) corresponding to SEQ ID NO: 33 (ELRMSS SYPTGLADVK AGPAQTLIRP QDMKGASRSP EDSSPDAARI RV) of the instant claims (see “Examples of Sequences” on Page 30 of instant specification and Sequence Listing on Page 52 of Struck). CT-proADM has the amino acid sequence of SEQ ID NO: 5 (RRR RRSLPEAGPG RTLVSSKPQA HGAPAPPSGS APHFL) corresponding to SEQ ID NO: 36 (RRR RRSLPEAGPG RTLVSSKPQA HGAPAPPSGS APHFL) of the instant claims (see “Examples of Sequences” on Page 30 of instant specification and Sequence Listing on Page 52 of Struck). Mature ADM (bio-ADM) has the amino acid sequence of SEQ ID NO: 1 (shown below) corresponding to SEQ ID NO: 34 recited in the instant claims (see “Examples of Sequences” on Page 30 of instant specification and Sequence Listing on Page 52 of Struck).
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It would have been obvious to one of ordinary skill in the art to further determine the levels of pro-ADM or fragments thereof—e.g. ADM-NH2, MR-proADM, or CT-proAMD- in a subject having refractory shock and initiate anti-ADM antibody therapy if the levels are above a predetermined threshold. One of ordinary skill in the art would have been motivated to do so since Xu suggests that assessing multiple biomarkers rather than a single biomarker helps improve diagnostic accuracy, and Morgenthaler provides guidance for using pro-ADM and/or fragments thereof to diagnose and treat shock with anti-ADM antibody therapy. In particular, Struck identifies the anti-ADM antibody HAM8101 for use in treating subjects having shock and further teaches determination of specific pro-ADM fragments including MR-proADM and CT-proADM to identify subjects having increased risk of outcome. Additionally, Struck teaches measurement of mature ADM-NH2 (bio-ADM) and disclosed healthy-subject reference values useful for distinguishing healthy vs diseased subjects via routine optimization. Indeed, the courts have stated that [W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); thus it would have been prima facie obvious to one of ordinary skill in the art to determine by routine experimentation the optimum threshold values of ADM-NH2, MR-proADM, or CT-proADM levels to arrive at the specific embodiments recited in the claims for identifying patients that would benefit from anti-ADM antibody therapy. Therefore, one of ordinary skill in the art would reasonably expect that determining the levels of pro-ADM or fragments thereof (e.g. ADM-NH2, MR-proADM, or CT-proADM) in a refractory shock patient and initiating anti-ADM antibody therapy when those levels are above a predetermined threshold can effectively treat refractory shock in said patient.
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.
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Claims 18, 26-31, and 44 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 61-67, 69, and 76-117 of copending Application No. 17416197 (reference application) in view of Bergmann (WO2017182561A1, of record) and Jentzer et al (Jentzer, Jacob C., et al. "Management of refractory vasodilatory shock." Chest 154.2 (2018): 416-426).
This is a provisional nonstatutory double patenting rejection.
The co-pending claims recite a method for the treatment of distributive shock [in a subject] comprising administering to the subject an angiotensin receptor agonist, wherein said subject has an amount of DPP3 protein and/or activity in a sample of bodily fluid that is above a predetermined threshold; and wherein the agonis is selected from the group consisting of SEQ ID NO: 13 (angiotensin II), SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16; SEQ ID NO: 17 (angiotensin II nonapeptide); SEQ ID NO: 18, SEQ ID NO: 19, and SEQ ID NO: 20 (co-pending claim 61). The agonist is administered in combination with an inhibitor of DPP3 activity such as an anti-DPP2 antibody or fragment thereof (co-pending claims 64-65). The DPP3 antibody comprises the heavy chain of SEQ ID NO: 11 corresponding to SEQ ID NO: 11 of the instant claims; and a light chain of SEQ ID NO: 12 corresponding to SEQ ID NO: 12 of the instant claims (co-pending claim 117). The heavy chain of SEQ ID NO: 11 fully comprises the VH chain of SEQ ID NO: 4 and the heavy chain CDRs of SEQ ID NOs: 7, 8, and 9 recited in the instant claims. The light chain of SEQ ID NO: 12 fully comprises the VL chain of SEQ ID NO: 4 and the light chain CDRs of SEQ ID NO: 10, KVS, and SEQ ID NO: 11 recited in instant claims. The anti-DPP3 antibody recited in both the co-pending and instant claims is clone AK1967, and thus the anti-DPP3 antibody of the co-pending claims have the CDRs and variable sequences recited in the instant claims (see “Sequences” on Pages 104-106 of copending specification as well as “Examples of Sequences” on Pages 89-91 of the instant specification).
The co-pending claims do not recite that the subject has refractory shock or determination of DPP3 levels in a body fluid sample above a predetermined threshold prior to administration of the DPP3 inhibitor.
However, Bergmann discloses a method for diagnosing a disease or condition accompanied by or related to necrotic processes in a subject comprising i) determining the amount of total or active DPP3 in a sample of bodily fluid obtained from the subject and ii) comparing the determined amount of total or active DPP3 to a predetermined threshold, wherein the subject is diagnosed as having a disease or condition accompanied by or related to necrotic processes if the determined amount is above the predetermined threshold (Page 22, Ln. 16-25). Further, disclosed is a method for treating said disease or condition in a subject comprising administering an inhibitor of DPP3 activity to the subject, wherein the subject has an elevated level of DPP3 above a predetermined threshold level (Page 39, Ln. 13-15; Page 40, Ln. 22-25). While it is not explicitly stated that septic shock is a disease/condition accompanied by or related to necrotic processes, elevated DPP3 levels relative to a predetermined threshold is a diagnostic criterion for said diseases or conditions; and it has been shown that patients with cardiogenic or septic shock exhibit elevated DPP3 plasma levels compared to healthy controls (Example 1). Thus, septic shock fall within the scope of necrotic-process related diseases or conditions wherein elevated DPP3 levels relative to a predetermined threshold can be used to diagnose a subject with septic shock and said subjects can be treated with a DPP3 activity inhibitor. The DPP3 activity inhibitor is, in some embodiments, an anti-DPP3 antibody or fragment thereof (Page, 36, Ln. 4-18). The threshold is predetermined by measuring DPP3 concentration and/or DPP3 activity in healthy controls and calculating, e.g., the 75th percentile, 90th percentile, or 95th percentile, wherein the upper border of a percentile defines the threshold for healthy versus diseased patients. In relation to said percentiles, the threshold that divides between healthy and diseased patients may be between 5 and 25 ng/ ml in plasma using a sandwich type anti-DPP3 immunoassay (Page 23, Ln. 4-16). It is further stated that a person skilled in the art knows a) how to determine thresholds from conducted previous studies and b) that a specific threshold value may depend on the cohort used for calculating a pre-determined threshold that can be later-on used in routine (Page 23, Ln. 18-24). Thus, the threshold value for DPP3 levels is recognized in the prior art as a result-effective variable to determine healthy vs diseased populations.
Jentzer further teaches that refractory shock is a lethal manifestation of cardiovascular failure defined by an inadequate hemodynamic response to high doses of vasopressor medications. Approximately 7% of critically ill patients will develop refractory shock, with short-term mortality exceeding 50% (Abstract), thus patients with refractory shock represent a patient population in need of therapeutic intervention.
It would have been obvious to one of ordinary skill in the art to modify the method of the co-pending claims such that DPP3 levels in a body fluid sample from the subject are first determined to be above a predetermined threshold prior to the administration of the anti-DPP3 antibody to a subject having refractory distributive shock. One of ordinary skill in the art would have been motivated to do so since elevated DPP3 levels are a diagnostic criterion for different forms of shock as taught by Bergmann, and a DPP3 inhibitor such the anti-DPP3 antibody of the co-pending claims can be used to treat shock in said subject. Further, refractory shock represents a severe subset of shock requiring therapeutic intervention as taught by Jentzer. Since a DPP3 inhibitor can be used to effectively treat shock, artisans would reasonably expect that patients with refractory shock would likewise receive therapeutic benefit. Lastly, the courts have stated that [W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); thus it would have been prima facie obvious to one of ordinary skill in the art to determine by routine experimentation the optimum threshold values of DPP3 levels to arrive at the specific embodiments recited in the claims for identifying and treating patients having refractory shock. Therefore, one of ordinary skill in the art to administer the anti-DPP3 antibody to treat refractory distributive shock in a subject determined to have DPP3 levels above a predetermined threshold.
Claims 19 and 32-35 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 61-67, 69, and 76-117 of copending Application No. 17416197 (reference application) in view of Bergmann and Jentzer, as applied to claims 18, 26-31, and 44 above, and further in view of Chawla (US20170196931A1).
This is a provisional nonstatutory double patenting rejection.
The teachings of the co-pending claims in view of Bergmann and Jentzer have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the DPP3 inhibitor is administered in combination with an angiotensin receptor agonist recited in the claims including angiotensin I, II, III, IV and analogues thereof.
However, Chawla teaches that angiotensinogen, Angiotensin I, Angiotensin II, angiotensin III, and angiotensin IV are hormones naturally produced by the body that regulate blood pressure via vasoconstriction and sodium reabsorption (Para. 0005) and thus discloses methods of treating hypotension (such as catecholamine-resistant hypertension) in a patient comprising administering an angiotensin therapeutic agent such as angiotensin I, angiotensin II, angiotensin III, angiotensin IV, or analogues thereof (Para. 0006-0007), wherein the patient has cardiogenic, distributive, or septic shock (Para. 0047). The angiotensin II is preferably 5-L-isoleucine angiotensin II (or human angiotensin II) having the sequence set forth in SEQ ID NO: (DRVYIHPF) corresponding to SEQ ID NO: 13 (DRVYIHPF) (Para. 0039 and 0068). Angiotensin II analogues contemplated for use include 5-L-valine angiotensin II [SEQ ID NO: 2, DRVYVHPF)] corresponding to SEQ ID NO: 14 (DRVYVHPF) of the instant claims; [Asn1-Phe4-]-angiotensin II [SEQ ID NO: 3 (NRVFIHPF)] corresponding to SEQ ID NO: 15 (NRVFIHPF) of the instant claims; angiotensin II nonapeptide [SEQ ID NO: 4 (NRVYYVHPF)] corresponding to SEQ ID NO: 17 (NRVYYVHPF) of the instant claims; [Asn1-Ile5-Ile8]-angiotensin II [SEQ ID NO:5 (NRVYIHPI)] corresponding to SEQ ID NO: SEQ ID NO: 18 (NRVYIHPI) of the instant claims; [Asn1-Ile5-Ala8]-angiotensin II [SEQ ID NO:6 (NRVYIHPA)] corresponding to SEQ ID NO: 19 (NRVYIHPA) of the instant claims; and [Asn1-diiodoTyr4-Ile5]-angiotensin II [SEQ ID NO:7 (NRVYIHPF)] corresponding to SEQ ID NO: 20 (NRVYIHPF) of the instant claims (Para. 0039 and 0068). The angiotensin III preferably has the sequence set forth in SEQ ID NO: 8 (or human angiotensin III) (RVYIHPF) corresponding to SEQ ID NO: (RVYIHPF) of the instant claims. The angiotensin III analogues also contemplated for use include 4-valine angiotensin III [SEQ ID NO: 9 (RVYVHPF)] corresponding to SEQ ID NO: 22 (RVYVHPF) of the instant claims; [Phe3]-angiotensin III [SEQ ID NO:10 (RVFIHPF)] corresponding to SEQ ID NO: 23 of the instant claims; [Ile4-Ala7]-angiotensin III [SEQ ID NO:11 (RVYIHPA) corresponding to SEQ ID NO: 24 of the instant claims (RVYIHPA); and [diiodoTyr3-Ile4]-angiotensin III [SEQ ID NO:12 (RVYIHPF)] corresponding to SEQ ID NO: 25 of the instant claims (Para. 0040 and Para. 0070). The angiotensin IV preferably has the sequence set forth in SEQ ID NO: 13 (or human angiotensin IV) (VYIHPF) corresponding to both SEQ ID NO: 16 (angiotensin II hexapeptide - VYIHPF) and SEQ ID NO: 26 (VYIHPF) of the instant claims. The angiotensin IV analogues contemplated for use include Val3 -angiotensin IV [SEQ ID NO: 14 (VYVHPF)] corresponding to SEQ ID NO: 27 (VYVHPF) of the instant claims; [Phe2]-angiotensin IV [SEQ ID NO:15 (VFIHPF)] corresponding to SEQ ID NO: 28 (VFIHPF) of the instant claims; [Ile3-Ala6]-angiotensin IV [SEQ ID NO:16 (VYIHPA)] corresponding to SEQ ID NO: 29 (VYIHPA) of the instant claims; and [diiodoTyr2-Ile3]-angiotensin IV [SEQ ID NO:17 (VYIHPF)] corresponding to SEQ ID NO: 30 (VYIHPF) of the instant claims (Para. 0041 and Para. 0072) (see also Examples of Sequences on Pages 91-92 of the instant specification).
It would have been obvious to one of ordinary skill in the art to modify the method of the co-pending claims such that administer an angiotensin receptor agonist such as angiotensin I, II, III, IV, or an analogue thereof in combination with an inhibitor of DPP3 activity to a subject having an elevated DPP3 level relative to a predetermined threshold, a characteristic of necrotic-related processes such as cardiogenic and septic shock. One of ordinary skill in the art would have been motivated to do so since angiotensin I, II, III, IV and analogues thereof regulate blood pressure via vasoconstriction and sodium reabsorption and thus can be used to effectively treat hypotension in patients suffering from various forms of shock (e.g. cardiogenic, distributive, or septic shock) in patients, including hypotension that is resistant (or refractory) to other treatment modalities (e.g. catecholamines) as taught by Chawla. Therefore, one of ordinary skill in the art would reasonably expect that administering angiotensin I, II, III, IV or an analogue thereof angiotensin II in combination with an DPP3 activity inhibitor to effectively treat a shock in a subject having elevated DPP3 levels relative to a predetermined threshold.
Claims 22 and 36-43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 61-67, 69, and 76-117 of copending Application No. 17416197 (reference application) in view of Bergmann, Jentzer, and Chawla as applied to claims 18, 19, 18, 26-35, and 44 above, and further in view of Xu et al (Xu, Tu, et al. "Flexible combination of multiple diagnostic biomarkers to improve diagnostic accuracy." BMC medical research methodology 15.1 (2015): 94, of record), hereinafter Xu, Morgenthaler et al (EP1619505B1, of record), hereinafter Morgenthaler, and Struck et al (WO2019077082A1), hereinafter Struck.
This is a provisional nonstatutory double patenting rejection.
The teachings of co-pending claims in view of Bergmann, Jentzer, and Chawla have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that in that it is not specifically taught that the level of pro-adrenomedullin or fragments thereof in a sample of plasma is also determined and treatment with an anti-ADM antibody or fragment thereof is initiated when the level is above a predetermined threshold or treatment with the anti-ADM antibody is withheld/terminated if the determined level of pro-adrenomedullin or fragments thereof is below said predetermined threshold, wherein the anti-ADM antibody has the CDRs recited in the instant claims and the predetermined threshold level of pro-ADM comprises ADM-NH2 in a range of 50 pg/ml – 250 pg/mL/ MR-proADM in a range of 0.5 nmol/L and 3 nmol/L; or CT-proADM in a range of 85 pmol/L – 500 pmol/L.
However, Xu teaches that diagnosis based on multiple biomarkers assessed in an individual rather a single biomarker improves diagnostic accuracy (Abstract and 3rd paragraph under Introduction).
Morgenthaler further teaches determining the concentration of pro-adrenomedullin (pro-ADM) or physiologically occurring fragments thereof in a body fluid sample from a critically ill patient to identify a life-threatening crisis requiring intervention, including sepsis and septic shock, and to assess mortality risk in diseases such as sepsis and septic shock (Abstract, Para. 0002, 0003, 0025, and 0028–0031). Further disclosed are specific cut-off values for interpreting such measurements in septic ICU patients where values above 8 nmol/L identify patients that have greatly increased mortality risk (para. 0042–0044). When pro-ADM levels are critically high, therapeutic intervention is warranted via administration of adrenomedullin antagonists such as antibodies that bind ADM and block its receptor interaction (e.g. antibodies to adrenomedullin that block its receptor binding sites: “immunological neutralization”) to treat conditions such as septic shock (para. 0055–0057, 0060, and 0066). Accordingly, Morgenthaler describes measuring pro-ADM in shock patients, comparing the level to a disclosed threshold, and initiating treatment with an anti-ADM antibody when the level exceeds that threshold.
Struck further teaches the anti-ADM antibody HAM8101 (adrecizumab) for use in treating subjects suffering from shock (e.g. sepsis/septic shock), wherein HAM8101 comprises the heavy chain of SEQ ID NO: 26 and the light chain of SEQ ID NO: 27 (Page 6, Ln. 26-31 to Page 7, Ln. 1-2; Page 7, Ln. 13-15; Page 19, Ln. 4-6; Page 13, Ln. 15-32; Example 1, Page 44). The heavy chain of adrecizumab fully comprises the CDRs of SEQ ID NOs: 38-40 and the VH chain of SEQ ID NO: 44 recited in the instant claims. The light chain of adrecizumab fully comprises the CDRs of SEQ ID NO: 41, RVS, SEQ ID NO: 42 of the instant claims. HAM8101 is identified as adrecizumab and thus has all of the sequences recited in the instant claims (see “Examples of Seqeunces on Page 94 of instant specification). Further disclosed is the determination of specific proADM-derived biomarkers including MR-proADM and CT-proADM (Page 6). Elevated levels of these pro-ADM fragments above a certain threshold are described as correlating with enhanced risk of adverse outcome (Page 28, Ln. 4-11). For plasma MR-proADM, the threshold is between 0.5 to 1.5 nmol/L, preferably 0.7 to 1 nmol/L, and most preferably is 0.8 nmol/L (Page 27, Ln. 1-3). For plasma CT-proADM, the threshold is between 85 to 350 pmol/L, preferably between 100 to 200 pmol/L, and most preferably is 150 pmol/L (Page 27, Ln. 5-7). Additionally, healthy-subject reference values for plasma mature ADM-NH2 (or bio-ADM) levels are also taught, including a median value of about 24.7 pg/mL, a lowest value of about 11 pg/ml and a 99th percentile value at about 43 pg/ml (Page 30, Ln. 25-29). These disclosed reference values can thus be used to distinguish healthy subjects from subjects having elevated ADM-NH2 levels associated with disease and/or shock states via routine optimization. MR-proADM has the amino acid sequence of SEQ ID NO: 4 (ELRMSS SYPTGLADVK AGPAQTLIRP QDMKGASRSP EDSSPDAARI RV) corresponding to SEQ ID NO: 33 (ELRMSS SYPTGLADVK AGPAQTLIRP QDMKGASRSP EDSSPDAARI RV) of the instant claims (see “Examples of Sequences” on Page 30 of instant specification and Sequence Listing on Page 52 of Struck). CT-proADM has the amino acid sequence of SEQ ID NO: 5 (RRR RRSLPEAGPG RTLVSSKPQA HGAPAPPSGS APHFL) corresponding to SEQ ID NO: 36 (RRR RRSLPEAGPG RTLVSSKPQA HGAPAPPSGS APHFL) of the instant claims (see “Examples of Sequences” on Page 30 of instant specification and Sequence Listing on Page 52 of Struck). Mature ADM (bio-ADM) has the amino acid sequence of SEQ ID NO: 1 (shown below) corresponding to SEQ ID NO: 34 recited in the instant claims (see “Examples of Sequences” on Page 30 of instant specification and Sequence Listing on Page 52 of Struck).
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It would have been obvious to one of ordinary skill in the art to modify the method of the co-pending claims in view of Bergmann, Jentzer, and Chawla such that the levels of pro-ADM or fragments thereof—e.g. ADM-NH2, MR-proADM, or CT-proAMD- in a subject having refractory shock are further determined and anti-ADM antibody therapy is initiated if the levels are above a predetermined threshold. One of ordinary skill in the art would have been motivated to do so since Xu suggests that assessing multiple biomarkers rather than a single biomarker helps improve diagnostic accuracy, and Morgenthaler provides guidance for using pro-ADM and/or fragments thereof to diagnose and treat shock with anti-ADM antibody therapy. In particular, Struck identifies the anti-ADM antibody HAM8101 for use in treating subjects having shock and further teaches determination of specific pro-ADM fragments including MR-proADM and CT-proADM to identify subjects having increased risk of outcome. Additionally, Struck teaches measurement of mature ADM-NH2 (bio-ADM) and disclosed healthy-subject reference values useful for distinguishing healthy vs diseased subjects via routine optimization. Indeed, the courts have stated that [W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); thus it would have been prima facie obvious to one of ordinary skill in the art to determine by routine experimentation the optimum threshold values of ADM-NH2, MR-proADM, or CT-proADM levels to arrive at the specific embodiments recited in the claims for identifying patients that would benefit from anti-ADM antibody therapy. Therefore, one of ordinary skill in the art would reasonably expect that further determining the levels of pro-ADM or fragments thereof (e.g. ADM-NH2, MR-proADM, or CT-proADM) in a refractory shock patient and initiating anti-ADM antibody therapy when those levels are above a predetermined threshold can effectively treat refractory shock in said patient.
Claims 18, 26-31, and 44 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of copending Application No. 19136254 (reference application) in view of Jentzer et al (Jentzer, Jacob C., et al. "Management of refractory vasodilatory shock." Chest 154.2 (2018): 416-426), hereinafter Jentzer.
This is a provisional nonstatutory double patenting rejection.
The co-pending claims recite an inhibitor of the activity of DPP3 for use in therapy or intervention in a critically ill patient with a reduction in pulmonary function for the improvement of pulmonary function, wherein the critically ill patient is suffering from a type of shock (e.g. cardiogenic, septic, or anaphylactic) and has a DPP3 level in a sample of bodily fluid above a predetermined threshold (co-pending claims 1, 2, and 10). The pre-determined threshold level of DPP3 in a sample of bodily fluid is between 20 and 120 ng/mL, preferably between 30 and 80 ng/mL, more preferably between 35 and 60 ng/mL, and most preferably the threshold is 40 ng/mL (co-pending claim 3). The inhibitor of DPP3 activity is, for example, an anti-DPP3 antibody or fragment thereof (co-pending claim 13), wherein the anti-DPP3 antibody comprises the heavy chain of SEQ ID NO: 12 corresponding to SEQ ID NO: 11 of the instant claims and the light chain of SEQ ID NO: 13 corresponding to SEQ ID NO: 12 of the instant claims (co-pending claim 18). The heavy chain of SEQ ID NO: 12 fully comprises the VH chain of SEQ ID NO: 4 and the heavy chain CDRs of SEQ ID NOs: 7, 8, and 9 recited in the instant claims. The light chain of SEQ ID NO: 13 fully comprises the VL chain of SEQ ID NO: 4 and the light chain CDRs of SEQ ID NO: 10, KVS, and SEQ ID NO: 11 recited in instant claims. The anti-DPP3 antibody recited in both the co-pending and instant claims is clone AK1967, and thus the anti-DPP3 antibody of the co-pending claims have the CDRs and variable sequences recited in the instant claims (see “Sequences” on Pages 60-62 of copending specification as well as “Examples of Sequences” on Pages 89-91 of the instant specification).
The co-pending claims do not teach that the subject has refractory shock.
However, Jentzer teaches that refractory shock is a lethal manifestation of cardiovascular failure defined by an inadequate hemodynamic response to high doses of vasopressor medications. Approximately 7% of critically ill patients will develop refractory shock, with short-term mortality exceeding 50% (Abstract), thus patients with refractory shock represent a patient population in need of therapeutic intervention.
It would have been obvious to one of ordinary skill in the art to modify the method of treating shock in a subject recited by the co-pending claims such that the patient has refractory shock. One of ordinary skill in the art would have been motivated to do so since refractory shock is a severe subset of shock requiring therapeutic intervention; and the anti-DPP3 antibody of the co-pending claims can be used to treat shock. As such, administration of anti-DPP3 antibody would likewise be beneficial in the subset of patients having refractory shock. Further, the courts have stated that [W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); thus it would have been prima facie obvious to one of ordinary skill in the art to determine by routine experimentation the optimum threshold values of DPP3 levels to arrive at the specific embodiments recited in the claims for identifying and treating patients having refractory shock. Therefore one of ordinary skill in the art would reasonably expect that administration of the anti-DPP3 antibody of the co-pending claims to be therapeutically beneficial in the treatment of patients with refractory shock identified as having DPP3 levels above a predetermined threshold.
Claims 19 and 32-35 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of copending Application No. 19136254 (reference application) in view of Jentzer, as applied to claims 18, 26-31, and 44 above, and further in view of Chawla (US20170196931A1).
This is a provisional nonstatutory double patenting rejection.
The teachings of the co-pending claims in view of Jentzer have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the DPP3 inhibitor is administered in combination with an angiotensin receptor agonist recited in the claims including angiotensin I, II, III, IV and analogues thereof.
However, Chawla teaches that angiotensinogen, Angiotensin I, Angiotensin II, angiotensin III, and angiotensin IV are hormones naturally produced by the body that regulate blood pressure via vasoconstriction and sodium reabsorption (Para. 0005) and thus discloses methods of treating hypotension (such as catecholamine-resistant hypertension) in a patient comprising administering an angiotensin therapeutic agent such as angiotensin I, angiotensin II, angiotensin III, angiotensin IV, or analogues thereof (Para. 0006-0007), wherein the patient has cardiogenic, distributive, or septic shock (Para. 0047). The angiotensin II is preferably 5-L-isoleucine angiotensin II (or human angiotensin II) having the sequence set forth in SEQ ID NO: (DRVYIHPF) corresponding to SEQ ID NO: 13 (DRVYIHPF) (Para. 0039 and 0068). Angiotensin II analogues contemplated for use include 5-L-valine angiotensin II [SEQ ID NO: 2, DRVYVHPF)] corresponding to SEQ ID NO: 14 (DRVYVHPF) of the instant claims; [Asn1-Phe4-]-angiotensin II [SEQ ID NO: 3 (NRVFIHPF)] corresponding to SEQ ID NO: 15 (NRVFIHPF) of the instant claims; angiotensin II nonapeptide [SEQ ID NO: 4 (NRVYYVHPF)] corresponding to SEQ ID NO: 17 (NRVYYVHPF) of the instant claims; [Asn1-Ile5-Ile8]-angiotensin II [SEQ ID NO:5 (NRVYIHPI)] corresponding to SEQ ID NO: SEQ ID NO: 18 (NRVYIHPI) of the instant claims; [Asn1-Ile5-Ala8]-angiotensin II [SEQ ID NO:6 (NRVYIHPA)] corresponding to SEQ ID NO: 19 (NRVYIHPA) of the instant claims; and [Asn1-diiodoTyr4-Ile5]-angiotensin II [SEQ ID NO:7 (NRVYIHPF)] corresponding to SEQ ID NO: 20 (NRVYIHPF) of the instant claims (Para. 0039 and 0068). The angiotensin III preferably has the sequence set forth in SEQ ID NO: 8 (or human angiotensin III) (RVYIHPF) corresponding to SEQ ID NO: (RVYIHPF) of the instant claims. The angiotensin III analogues also contemplated for use include 4-valine angiotensin III [SEQ ID NO: 9 (RVYVHPF)] corresponding to SEQ ID NO: 22 (RVYVHPF) of the instant claims; [Phe3]-angiotensin III [SEQ ID NO:10 (RVFIHPF)] corresponding to SEQ ID NO: 23 of the instant claims; [Ile4-Ala7]-angiotensin III [SEQ ID NO:11 (RVYIHPA) corresponding to SEQ ID NO: 24 of the instant claims (RVYIHPA); and [diiodoTyr3-Ile4]-angiotensin III [SEQ ID NO:12 (RVYIHPF)] corresponding to SEQ ID NO: 25 of the instant claims (Para. 0040 and Para. 0070). The angiotensin IV preferably has the sequence set forth in SEQ ID NO: 13 (or human angiotensin IV) (VYIHPF) corresponding to both SEQ ID NO: 16 (angiotensin II hexapeptide - VYIHPF) and SEQ ID NO: 26 (VYIHPF) of the instant claims. The angiotensin IV analogues contemplated for use include Val3 -angiotensin IV [SEQ ID NO: 14 (VYVHPF)] corresponding to SEQ ID NO: 27 (VYVHPF) of the instant claims; [Phe2]-angiotensin IV [SEQ ID NO:15 (VFIHPF)] corresponding to SEQ ID NO: 28 (VFIHPF) of the instant claims; [Ile3-Ala6]-angiotensin IV [SEQ ID NO:16 (VYIHPA)] corresponding to SEQ ID NO: 29 (VYIHPA) of the instant claims; and [diiodoTyr2-Ile3]-angiotensin IV [SEQ ID NO:17 (VYIHPF)] corresponding to SEQ ID NO: 30 (VYIHPF) of the instant claims (Para. 0041 and Para. 0072) (see also Examples of Sequences on Pages 91-92 of the instant specification).
It would have been obvious to one of ordinary skill in the art to modify the method of the co-pending claims such that administer an angiotensin receptor agonist such as angiotensin I, II, III, IV, or an analogue thereof in combination with an inhibitor of DPP3 activity to a subject having an elevated DPP3 level relative to a predetermined threshold, a characteristic of necrotic-related processes such as cardiogenic and septic shock. One of ordinary skill in the art would have been motivated to do so since angiotensin I, II, III, IV and analogues thereof regulate blood pressure via vasoconstriction and sodium reabsorption and thus can be used to effectively treat hypotension in patients suffering from various forms of shock (e.g. cardiogenic, distributive, or septic shock) in patients, including hypotension that is resistant (or refractory) to other treatment modalities (e.g. catecholamines) as taught by Chawla. Therefore, one of ordinary skill in the art would reasonably expect that administering angiotensin I, II, III, IV or an analogue thereof angiotensin II in combination with an DPP3 activity inhibitor to effectively treat a shock in a subject having elevated DPP3 levels relative to a predetermined threshold.
Claims 22 and 36-43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of copending Application No. 19136254 (reference application) in view of Jentzer and Chawla, as applied to claims 18, 19, 18, 26-35, and 44 above, and further in view of Xu et al (Xu, Tu, et al. "Flexible combination of multiple diagnostic biomarkers to improve diagnostic accuracy." BMC medical research methodology 15.1 (2015): 94, of record), hereinafter Xu, Morgenthaler et al (EP1619505B1, of record), hereinafter Morgenthaler, and Struck et al (WO2019077082A1), hereinafter Struck.
This is a provisional nonstatutory double patenting rejection.
The teachings of co-pending claims in view of Jentzer and Chawla have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the level of pro-adrenomedullin or fragments thereof in a sample of plasma is also determined and treatment with an anti-ADM antibody or fragment thereof is initiated when the level is above a predetermined threshold or treatment with the anti-ADM antibody is withheld/terminated if the determined level of pro-adrenomedullin or fragments thereof is below said predetermined threshold, wherein the anti-ADM antibody has the CDRs recited in the instant claims and the predetermined threshold level of pro-ADM comprises ADM-NH2 in a range of 50 pg/ml – 250 pg/mL/ MR-proADM in a range of 0.5 nmol/L and 3 nmol/L; or CT-proADM in a range of 85 pmol/L – 500 pmol/L.
However, Xu teaches that diagnosis based on multiple biomarkers assessed in an individual rather a single biomarker improves diagnostic accuracy (Abstract and 3rd paragraph under Introduction).
Morgenthaler further teaches determining the concentration of pro-adrenomedullin (pro-ADM) or physiologically occurring fragments thereof in a body fluid sample from a critically ill patient to identify a life-threatening crisis requiring intervention, including sepsis and septic shock, and to assess mortality risk in diseases such as sepsis and septic shock (Abstract, Para. 0002, 0003, 0025, and 0028–0031). Further disclosed are specific cut-off values for interpreting such measurements in septic ICU patients where values above 8 nmol/L identify patients that have greatly increased mortality risk (para. 0042–0044). When pro-ADM levels are critically high, therapeutic intervention is warranted via administration of adrenomedullin antagonists such as antibodies that bind ADM and block its receptor interaction (e.g. antibodies to adrenomedullin that block its receptor binding sites: “immunological neutralization”) to treat conditions such as septic shock (para. 0055–0057, 0060, and 0066). Accordingly, Morgenthaler describes measuring pro-ADM in shock patients, comparing the level to a disclosed threshold, and initiating treatment with an anti-ADM antibody when the level exceeds that threshold.
Struck further teaches the anti-ADM antibody HAM8101 (adrecizumab) for use in treating subjects suffering from shock (e.g. sepsis/septic shock), wherein HAM8101 comprises the heavy chain of SEQ ID NO: 26 and the light chain of SEQ ID NO: 27 (Page 6, Ln. 26-31 to Page 7, Ln. 1-2; Page 7, Ln. 13-15; Page 19, Ln. 4-6; Page 13, Ln. 15-32; Example 1, Page 44). The heavy chain of adrecizumab fully comprises the CDRs of SEQ ID NOs: 38-40 and the VH chain of SEQ ID NO: 44 recited in the instant claims. The light chain of adrecizumab fully comprises the CDRs of SEQ ID NO: 41, RVS, SEQ ID NO: 42 of the instant claims. HAM8101 is identified as adrecizumab and thus has all of the sequences recited in the instant claims (see “Examples of Seqeunces on Page 94 of instant specification). Further disclosed is the determination of specific proADM-derived biomarkers including MR-proADM and CT-proADM (Page 6). Elevated levels of these pro-ADM fragments above a certain threshold are described as correlating with enhanced risk of adverse outcome (Page 28, Ln. 4-11). For plasma MR-proADM, the threshold is between 0.5 to 1.5 nmol/L, preferably 0.7 to 1 nmol/L, and most preferably is 0.8 nmol/L (Page 27, Ln. 1-3). For plasma CT-proADM, the threshold is between 85 to 350 pmol/L, preferably between 100 to 200 pmol/L, and most preferably is 150 pmol/L (Page 27, Ln. 5-7). Additionally, healthy-subject reference values for plasma mature ADM-NH2 (or bio-ADM) levels are also taught, including a median value of about 24.7 pg/mL, a lowest value of about 11 pg/ml and a 99th percentile value at about 43 pg/ml (Page 30, Ln. 25-29). These disclosed reference values can thus be used to distinguish healthy subjects from subjects having elevated ADM-NH2 levels associated with disease and/or shock states via routine optimization. MR-proADM has the amino acid sequence of SEQ ID NO: 4 (ELRMSS SYPTGLADVK AGPAQTLIRP QDMKGASRSP EDSSPDAARI RV) corresponding to SEQ ID NO: 33 (ELRMSS SYPTGLADVK AGPAQTLIRP QDMKGASRSP EDSSPDAARI RV) of the instant claims (see “Examples of Sequences” on Page 30 of instant specification and Sequence Listing on Page 52 of Struck). CT-proADM has the amino acid sequence of SEQ ID NO: 5 (RRR RRSLPEAGPG RTLVSSKPQA HGAPAPPSGS APHFL) corresponding to SEQ ID NO: 36 (RRR RRSLPEAGPG RTLVSSKPQA HGAPAPPSGS APHFL) of the instant claims (see “Examples of Sequences” on Page 30 of instant specification and Sequence Listing on Page 52 of Struck). Mature ADM (bio-ADM) has the amino acid sequence of SEQ ID NO: 1 (shown below) corresponding to SEQ ID NO: 34 recited in the instant claims (see “Examples of Sequences” on Page 30 of instant specification and Sequence Listing on Page 52 of Struck).
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It would have been obvious to one of ordinary skill in the art to modify the method of the co-pending claims in view of Jentzer and Chawla such that the levels of pro-ADM or fragments thereof—e.g. ADM-NH2, MR-proADM, or CT-proAMD- in a subject having refractory shock are further determined and anti-ADM antibody therapy is initiated if the levels are above a predetermined threshold. One of ordinary skill in the art would have been motivated to do so since Xu suggests that assessing multiple biomarkers rather than a single biomarker helps improve diagnostic accuracy, and Morgenthaler provides guidance for using pro-ADM and/or fragments thereof to diagnose and treat shock with anti-ADM antibody therapy. In particular, Struck identifies the anti-ADM antibody HAM8101 for use in treating subjects having shock and further teaches determination of specific pro-ADM fragments including MR-proADM and CT-proADM to identify subjects having increased risk of outcome. Additionally, Struck teaches measurement of mature ADM-NH2 (bio-ADM) and disclosed healthy-subject reference values useful for distinguishing healthy vs diseased subjects via routine optimization. Indeed, the courts have stated that [W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); thus it would have been prima facie obvious to one of ordinary skill in the art to determine by routine experimentation the optimum threshold values of ADM-NH2, MR-proADM, or CT-proADM levels to arrive at the specific embodiments recited in the claims for identifying patients that would benefit from anti-ADM antibody therapy. Therefore, one of ordinary skill in the art would reasonably expect that further determining the levels of pro-ADM or fragments thereof (e.g. ADM-NH2, MR-proADM, or CT-proADM) in a refractory shock patient and initiating anti-ADM antibody therapy when those levels are above a predetermined threshold can effectively treat refractory shock in said patient.
Claims 18, 26-31, and 44 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 16-18 and 20-95 of copending Application No. 17984611 (reference application) in view of Bergmann (WO2017182561A1) and Jentzer et al (Jentzer, Jacob C., et al. "Management of refractory vasodilatory shock." Chest 154.2 (2018): 416-426), hereinafter Jentzer.
This is a provisional nonstatutory double patenting rejection.
The co-pending claims recite a method for the treatment of septic shock in a patient comprising administering to the subject an anti-DPP3 monoclonal antibody comprising the heavy chain of SEQ ID NO: 12 corresponding to SEQ ID NO: 11 of the instant claims; and the light chain of SEQ ID NO: 13 corresponding to SEQ ID NO: 12 of the instant claims (co-pending claims 16, 21, 22, and 39). The heavy chain of SEQ ID NO: 12 fully comprises the VH chain of SEQ ID NO: 4 and the heavy chain CDRs of SEQ ID NOs: 7, 8, and 9 recited in the instant claims. The light chain of SEQ ID NO: 13 fully comprises the VL chain of SEQ ID NO: 4 and the light chain CDRs of SEQ ID NO: 10, KVS, and SEQ ID NO: 11 recited in instant claims. The anti-DPP3 antibody recited in both the co-pending and instant claims is clone AK1967, and thus the anti-DPP3 antibody of the co-pending claims have the CDRs and variable sequences recited in the instant claims (see Sequence Listing Pages 88-89 of copending specification as well as “Examples of Sequences” on Pages 89-91 of the instant specification). Per the co-pending specification, the anti-DPP3 antibody is clone AK1967, which can inhibit the activity of DPP3 (see Examples 1-3, Pages 70-78; Sequence Listing, Pages 88-89).
The co-pending claims do not recite that the subject has refractory shock or determination of DPP3 levels in a body fluid sample above a predetermined threshold prior to administration of the DPP3 inhibitor.
However, Bergmann discloses a method for diagnosing a disease or condition accompanied by or related to necrotic processes in a subject comprising i) determining the amount of total or active DPP3 in a sample of bodily fluid obtained from the subject and ii) comparing the determined amount of total or active DPP3 to a predetermined threshold, wherein the subject is diagnosed as having a disease or condition accompanied by or related to necrotic processes if the determined amount is above the predetermined threshold (Page 22, Ln. 16-25). Further, disclosed is a method for treating said disease or condition in a subject comprising administering an inhibitor of DPP3 activity to the subject, wherein the subject has an elevated level of DPP3 above a predetermined threshold level (Page 39, Ln. 13-15; Page 40, Ln. 22-25). While it is not explicitly stated that septic shock is a disease/condition accompanied by or related to necrotic processes, elevated DPP3 levels relative to a predetermined threshold is a diagnostic criterion for said diseases or conditions; and it has been shown that patients with cardiogenic or septic shock exhibit elevated DPP3 plasma levels compared to healthy controls (Example 1). Thus, septic shock fall within the scope of necrotic-process related diseases or conditions wherein elevated DPP3 levels relative to a predetermined threshold can be used to diagnose a subject with septic shock and said subjects can be treated with a DPP3 activity inhibitor. The DPP3 activity inhibitor is, in some embodiments, an anti-DPP3 antibody or fragment thereof (Page, 36, Ln. 4-18). The threshold is predetermined by measuring DPP3 concentration and/or DPP3 activity in healthy controls and calculating, e.g., the 75th percentile, 90th percentile, or 95th percentile, wherein the upper border of a percentile defines the threshold for healthy versus diseased patients. In relation to said percentiles, the threshold that divides between healthy and diseased patients may be between 5 and 25 ng/ ml in plasma using a sandwich type anti-DPP3 immunoassay (Page 23, Ln. 4-16). It is further stated that a person skilled in the art knows a) how to determine thresholds from conducted previous studies and b) that a specific threshold value may depend on the cohort used for calculating a pre-determined threshold that can be later-on used in routine (Page 23, Ln. 18-24). Thus, the threshold value for DPP3 levels is recognized in the prior art as a result-effective variable to determine healthy vs diseased populations
Jentzer further teaches that refractory shock is a lethal manifestation of cardiovascular failure defined by an inadequate hemodynamic response to high doses of vasopressor medications. Approximately 7% of critically ill patients will develop refractory shock, with short-term mortality exceeding 50% (Abstract), thus patients with refractory shock represent a patient population in need of therapeutic intervention.
It would have been obvious to one of ordinary skill in the art to modify the method of the co-pending claims such that DPP3 levels in a body fluid sample from the subject are first determined to be above a predetermined threshold prior to the administration of the anti-DPP3 antibody to a subject having refractory distributive shock. One of ordinary skill in the art would have been motivated to do so since elevated DPP3 levels are a diagnostic criterion for different forms of shock as taught by Bergmann, and a DPP3 inhibitor such the anti-DPP3 antibody of the co-pending claims can be used to treat shock in said subject. Further, refractory shock represents a severe subset of shock requiring therapeutic intervention as taught by Jentzer. Since a DPP3 inhibitor can be used to effectively treat shock, artisans would reasonably expect that patients with refractory shock would likewise receive therapeutic benefit. Lastly, the courts have stated that [W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); thus it would have been prima facie obvious to one of ordinary skill in the art to determine by routine experimentation the optimum threshold values of DPP3 levels to arrive at the specific embodiments recited in the claims for identifying and treating patients having refractory shock. Therefore, one of ordinary skill in the art to administer the anti-DPP3 antibody to treat refractory septic shock in a subject determined to have DPP3 levels above a predetermined threshold.
Claims 19 and 32-35 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 16-18 and 20-95 of copending Application No. 17984611 (reference application) in view of Bergmann and Jentzer, as applied to claims 18, 26-31, and 44 above, and further in view of Chawla (US20170196931A1).
This is a provisional nonstatutory double patenting rejection.
The teachings of the co-pending claims in view of Bergmann and Jentzer have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the DPP3 inhibitor is administered in combination with an angiotensin receptor agonist recited in the claims including angiotensin I, II, III, IV and analogues thereof.
However, Chawla teaches that angiotensinogen, Angiotensin I, Angiotensin II, angiotensin III, and angiotensin IV are hormones naturally produced by the body that regulate blood pressure via vasoconstriction and sodium reabsorption (Para. 0005) and thus discloses methods of treating hypotension (such as catecholamine-resistant hypertension) in a patient comprising administering an angiotensin therapeutic agent such as angiotensin I, angiotensin II, angiotensin III, angiotensin IV, or analogues thereof (Para. 0006-0007), wherein the patient has cardiogenic, distributive, or septic shock (Para. 0047). The angiotensin II is preferably 5-L-isoleucine angiotensin II (or human angiotensin II) having the sequence set forth in SEQ ID NO: (DRVYIHPF) corresponding to SEQ ID NO: 13 (DRVYIHPF) (Para. 0039 and 0068). Angiotensin II analogues contemplated for use include 5-L-valine angiotensin II [SEQ ID NO: 2, DRVYVHPF)] corresponding to SEQ ID NO: 14 (DRVYVHPF) of the instant claims; [Asn1-Phe4-]-angiotensin II [SEQ ID NO: 3 (NRVFIHPF)] corresponding to SEQ ID NO: 15 (NRVFIHPF) of the instant claims; angiotensin II nonapeptide [SEQ ID NO: 4 (NRVYYVHPF)] corresponding to SEQ ID NO: 17 (NRVYYVHPF) of the instant claims; [Asn1-Ile5-Ile8]-angiotensin II [SEQ ID NO:5 (NRVYIHPI)] corresponding to SEQ ID NO: SEQ ID NO: 18 (NRVYIHPI) of the instant claims; [Asn1-Ile5-Ala8]-angiotensin II [SEQ ID NO:6 (NRVYIHPA)] corresponding to SEQ ID NO: 19 (NRVYIHPA) of the instant claims; and [Asn1-diiodoTyr4-Ile5]-angiotensin II [SEQ ID NO:7 (NRVYIHPF)] corresponding to SEQ ID NO: 20 (NRVYIHPF) of the instant claims (Para. 0039 and 0068). The angiotensin III preferably has the sequence set forth in SEQ ID NO: 8 (or human angiotensin III) (RVYIHPF) corresponding to SEQ ID NO: (RVYIHPF) of the instant claims. The angiotensin III analogues also contemplated for use include 4-valine angiotensin III [SEQ ID NO: 9 (RVYVHPF)] corresponding to SEQ ID NO: 22 (RVYVHPF) of the instant claims; [Phe3]-angiotensin III [SEQ ID NO:10 (RVFIHPF)] corresponding to SEQ ID NO: 23 of the instant claims; [Ile4-Ala7]-angiotensin III [SEQ ID NO:11 (RVYIHPA) corresponding to SEQ ID NO: 24 of the instant claims (RVYIHPA); and [diiodoTyr3-Ile4]-angiotensin III [SEQ ID NO:12 (RVYIHPF)] corresponding to SEQ ID NO: 25 of the instant claims (Para. 0040 and Para. 0070). The angiotensin IV preferably has the sequence set forth in SEQ ID NO: 13 (or human angiotensin IV) (VYIHPF) corresponding to both SEQ ID NO: 16 (angiotensin II hexapeptide - VYIHPF) and SEQ ID NO: 26 (VYIHPF) of the instant claims. The angiotensin IV analogues contemplated for use include Val3 -angiotensin IV [SEQ ID NO: 14 (VYVHPF)] corresponding to SEQ ID NO: 27 (VYVHPF) of the instant claims; [Phe2]-angiotensin IV [SEQ ID NO:15 (VFIHPF)] corresponding to SEQ ID NO: 28 (VFIHPF) of the instant claims; [Ile3-Ala6]-angiotensin IV [SEQ ID NO:16 (VYIHPA)] corresponding to SEQ ID NO: 29 (VYIHPA) of the instant claims; and [diiodoTyr2-Ile3]-angiotensin IV [SEQ ID NO:17 (VYIHPF)] corresponding to SEQ ID NO: 30 (VYIHPF) of the instant claims (Para. 0041 and Para. 0072) (see also Examples of Sequences on Pages 91-92 of the instant specification).
It would have been obvious to one of ordinary skill in the art to modify the method of the co-pending claims such that administer an angiotensin receptor agonist such as angiotensin I, II, III, IV, or an analogue thereof in combination with an inhibitor of DPP3 activity to a subject having an elevated DPP3 level relative to a predetermined threshold, a characteristic of necrotic-related processes such as cardiogenic and septic shock. One of ordinary skill in the art would have been motivated to do so since angiotensin I, II, III, IV and analogues thereof regulate blood pressure via vasoconstriction and sodium reabsorption and thus can be used to effectively treat hypotension in patients suffering from various forms of shock (e.g. cardiogenic, distributive, or septic shock) in patients, including hypotension that is resistant (or refractory) to other treatment modalities (e.g. catecholamines) as taught by Chawla. Therefore, one of ordinary skill in the art would reasonably expect that administering angiotensin I, II, III, IV or an analogue thereof angiotensin II in combination with an DPP3 activity inhibitor to effectively treat a shock in a subject having elevated DPP3 levels relative to a predetermined threshold.
Claims 22 and 36-43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 16-18 and 20-95 of copending Application No. 17984611 (reference application) in view of Bergmann, Jentzer, and Chawla, as applied to claims 18, 19, 18, 26-35, and 44 above, and further in view of Xu et al (Xu, Tu, et al. "Flexible combination of multiple diagnostic biomarkers to improve diagnostic accuracy." BMC medical research methodology 15.1 (2015): 94, of record), hereinafter Xu, Morgenthaler et al (EP1619505B1, of record), hereinafter Morgenthaler, and Struck et al (WO2019077082A1), hereinafter Struck.
This is a provisional nonstatutory double patenting rejection.
The teachings of co-pending claims in view of Bergmann, Jentzer, and Chawla have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the level of pro-adrenomedullin or fragments thereof in a sample of plasma is also determined and treatment with an anti-ADM antibody or fragment thereof is initiated when the level is above a predetermined threshold or treatment with the anti-ADM antibody is withheld/terminated if the determined level of pro-adrenomedullin or fragments thereof is below said predetermined threshold, wherein the anti-ADM antibody has the CDRs recited in the instant claims and the predetermined threshold level of pro-ADM comprises ADM-NH2 in a range of 50 pg/ml – 250 pg/mL/ MR-proADM in a range of 0.5 nmol/L and 3 nmol/L; or CT-proADM in a range of 85 pmol/L – 500 pmol/L.
However, Xu teaches that diagnosis based on multiple biomarkers assessed in an individual rather a single biomarker improves diagnostic accuracy (Abstract and 3rd paragraph under Introduction).
Morgenthaler further teaches determining the concentration of pro-adrenomedullin (pro-ADM) or physiologically occurring fragments thereof in a body fluid sample from a critically ill patient to identify a life-threatening crisis requiring intervention, including sepsis and septic shock, and to assess mortality risk in diseases such as sepsis and septic shock (Abstract, Para. 0002, 0003, 0025, and 0028–0031). Further disclosed are specific cut-off values for interpreting such measurements in septic ICU patients where values above 8 nmol/L identify patients that have greatly increased mortality risk (para. 0042–0044). When pro-ADM levels are critically high, therapeutic intervention is warranted via administration of adrenomedullin antagonists such as antibodies that bind ADM and block its receptor interaction (e.g. antibodies to adrenomedullin that block its receptor binding sites: “immunological neutralization”) to treat conditions such as septic shock (para. 0055–0057, 0060, and 0066). Accordingly, Morgenthaler describes measuring pro-ADM in shock patients, comparing the level to a disclosed threshold, and initiating treatment with an anti-ADM antibody when the level exceeds that threshold.
Struck further teaches the anti-ADM antibody HAM8101 (adrecizumab) for use in treating subjects suffering from shock (e.g. sepsis/septic shock), wherein HAM8101 comprises the heavy chain of SEQ ID NO: 26 and the light chain of SEQ ID NO: 27 (Page 6, Ln. 26-31 to Page 7, Ln. 1-2; Page 7, Ln. 13-15; Page 19, Ln. 4-6; Page 13, Ln. 15-32; Example 1, Page 44). The heavy chain of adrecizumab fully comprises the CDRs of SEQ ID NOs: 38-40 and the VH chain of SEQ ID NO: 44 recited in the instant claims. The light chain of adrecizumab fully comprises the CDRs of SEQ ID NO: 41, RVS, SEQ ID NO: 42 of the instant claims. HAM8101 is identified as adrecizumab and thus has all of the sequences recited in the instant claims (see “Examples of Seqeunces on Page 94 of instant specification). Further disclosed is the determination of specific proADM-derived biomarkers including MR-proADM and CT-proADM (Page 6). Elevated levels of these pro-ADM fragments above a certain threshold are described as correlating with enhanced risk of adverse outcome (Page 28, Ln. 4-11). For plasma MR-proADM, the threshold is between 0.5 to 1.5 nmol/L, preferably 0.7 to 1 nmol/L, and most preferably is 0.8 nmol/L (Page 27, Ln. 1-3). For plasma CT-proADM, the threshold is between 85 to 350 pmol/L, preferably between 100 to 200 pmol/L, and most preferably is 150 pmol/L (Page 27, Ln. 5-7). Additionally, healthy-subject reference values for plasma mature ADM-NH2 (or bio-ADM) levels are also taught, including a median value of about 24.7 pg/mL, a lowest value of about 11 pg/ml and a 99th percentile value at about 43 pg/ml (Page 30, Ln. 25-29). These disclosed reference values can thus be used to distinguish healthy subjects from subjects having elevated ADM-NH2 levels associated with disease and/or shock states via routine optimization. MR-proADM has the amino acid sequence of SEQ ID NO: 4 (ELRMSS SYPTGLADVK AGPAQTLIRP QDMKGASRSP EDSSPDAARI RV) corresponding to SEQ ID NO: 33 (ELRMSS SYPTGLADVK AGPAQTLIRP QDMKGASRSP EDSSPDAARI RV) of the instant claims (see “Examples of Sequences” on Page 30 of instant specification and Sequence Listing on Page 52 of Struck). CT-proADM has the amino acid sequence of SEQ ID NO: 5 (RRR RRSLPEAGPG RTLVSSKPQA HGAPAPPSGS APHFL) corresponding to SEQ ID NO: 36 (RRR RRSLPEAGPG RTLVSSKPQA HGAPAPPSGS APHFL) of the instant claims (see “Examples of Sequences” on Page 30 of instant specification and Sequence Listing on Page 52 of Struck). Mature ADM (bio-ADM) has the amino acid sequence of SEQ ID NO: 1 (shown below) corresponding to SEQ ID NO: 34 recited in the instant claims (see “Examples of Sequences” on Page 30 of instant specification and Sequence Listing on Page 52 of Struck).
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It would have been obvious to one of ordinary skill in the art to modify the method of the co-pending claims in view of Bergmann, Jentzer, and Chawla such that the levels of pro-ADM or fragments thereof—e.g. ADM-NH2, MR-proADM, or CT-proAMD- in a subject having refractory shock are further determined and anti-ADM antibody therapy is initiated if the levels are above a predetermined threshold. One of ordinary skill in the art would have been motivated to do so since Xu suggests that assessing multiple biomarkers rather than a single biomarker helps improve diagnostic accuracy, and Morgenthaler provides guidance for using pro-ADM and/or fragments thereof to diagnose and treat shock with anti-ADM antibody therapy. In particular, Struck identifies the anti-ADM antibody HAM8101 for use in treating subjects having shock and further teaches determination of specific pro-ADM fragments including MR-proADM and CT-proADM to identify subjects having increased risk of outcome. Additionally, Struck teaches measurement of mature ADM-NH2 (bio-ADM) and disclosed healthy-subject reference values useful for distinguishing healthy vs diseased subjects via routine optimization. Indeed, the courts have stated that [W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); thus it would have been prima facie obvious to one of ordinary skill in the art to determine by routine experimentation the optimum threshold values of ADM-NH2, MR-proADM, or CT-proADM levels to arrive at the specific embodiments recited in the claims for identifying patients that would benefit from anti-ADM antibody therapy. Therefore, one of ordinary skill in the art would reasonably expect that further determining the levels of pro-ADM or fragments thereof (e.g. ADM-NH2, MR-proADM, or CT-proADM) in a refractory shock patient and initiating anti-ADM antibody therapy when those levels are above a predetermined threshold can effectively treat refractory shock in said patient.
Claims 18, 26-31, and 44 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-26 copending Application No. 18998052 (reference application) in view of Jentzer et al (Jentzer, Jacob C., et al. "Management of refractory vasodilatory shock." Chest 154.2 (2018): 416-426), hereinafter Jentzer, and Kaufmann et al (Kaufmann, Paul, et al. "A novel and highly efficient purification procedure for native human dipeptidyl peptidase 3 from human blood cell lysate." PLoS One 14.8 (2019): e0220866), hereinafter Kaufmann.
This is a provisional nonstatutory double patenting rejection.
The co-pending claims recite a method for the prevention of a DPP3 increase in a critically ill patient comprising determining the level of DPP3 in a sample of bodily fluid of the patient, comparing the determined level of DPP3 to a pre-determined threshold, and administering a DPP3 inhibitor if said determined level of DPP3 is above said pre-determined threshold (co-pending claim 18), wherein said critically ill patient is a patient with shock and/or a patient running into shock (co-pending claim 22). The predetermined threshold is between 30 ng/ml and 22 ng/ml; between 25 ng/ml and 22 ng/ml; or above 40 to 50 ng/ml (co-pending claims 2-4, 18-21 and 26). If the level of DPP3 is above a predetermined level, then ‘prevention of DPP3 increase’ in a subject with shock with a DPP3 inhibitor necessarily encompasses methods for treating shock.
The co-pending claims do not teach that the subject has refractory shock nor the anti-DPP3 antibody having the CDR or variable sequences recited in the instant claims.
However, Jentzer teaches that refractory shock is a lethal manifestation of cardiovascular failure defined by an inadequate hemodynamic response to high doses of vasopressor medications. Approximately 7% of critically ill patients will develop refractory shock, with short-term mortality exceeding 50% (Abstract), thus patients with refractory shock represent a patient population in need of therapeutic intervention.
Kaufmann teaches the anti-DPP3 monoclonal antibody AK1967 (see “Protein purity analysis and Western Blotting” section on Page 3). Per the instant specification, clone AK1967 comprises the heavy and light chain pair of SEQ ID NOs: 11 and 12, respectively. The heavy chain of SEQ ID NO: 11 fully comprises the VH chain of SEQ ID NO: 4 and the CDRs of SEQ ID NOs: 6-8. The light chain of SEQ ID NO: 12 fully comprises the VL chain of SEQ ID NO: 5 and the CDRs of SEQ ID NO: 9, KVS, and SEQ ID NO: 10 (see “Examples of Sequences” on Pages 89-90 of the instant specification). As such, the AK1967 antibody disclosed by Kaufmann comprises the CDR and variable sequences of the inhibitor of DPP3 activity recited in the instant claims. Further, per the PLOS Journal guidelines on the availability of materials (see attached ASM Journals Availability of Data and Materials), authors are expected “make all relevant materials that may be reasonably requested by others available without restriction upon publication of the work” (see Materials, Software and Code Sharing for PLOS Journals, OA.Appendix). Thus, the AK1967 clone was otherwise available to the public. Per the instant claims, the minimal structure required for an antibody to inhibit DPP3 activity is an HCDR3 of SEQ ID NO: 8 and a LCDR3 of SEQ ID NO: 10. Since the clone AK1967 has the same CDRs, variable domains, and heavy/light chains set forth in the claims, then said clone can be used to inhibit DPP3 activity.
It would have been obvious to one of ordinary skill in the art to modify the method of treating shock in a subject recited by the co-pending claims such that the patient has refractory shock. One of ordinary skill in the art would have been motivated to do so since refractory shock is a severe subset of shock requiring therapeutic intervention as taught by Jentzer; and the anti-DPP3 antibody of the co-pending claims can be used to treat shock. As such, administration of anti-DPP3 antibody would likewise be beneficial in the subset of patients having refractory shock. Further, the courts have stated that [W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); thus it would have been prima facie obvious to one of ordinary skill in the art to determine by routine experimentation the optimum threshold values of DPP3 levels to arrive at the specific embodiments recited in the claims for identifying and treating patients having refractory shock. Lastly, it would have been obvious to artisans to substitute anti-DPP3 antibody of Bergmann with the clone AK1967 disclosed by Kaufmann since they have the same structure and thus can be used for the same purpose. An express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213USPQ 532 (CCPA 1982). Therefore one of ordinary skill in the art would reasonably expect that administration of the anti-DPP3 antibody of the co-pending claims to be therapeutically beneficial in the treatment of patients with refractory shock identified as having DPP3 levels above a predetermined threshold.
Claims 19 and 32-35 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-26 copending Application No. 18998052 (reference application) in view of Jenzter and Kauffmann, as applied to claims 18, 26-31, and 44 above, and further in view of Chawla (US20170196931A1).
This is a provisional nonstatutory double patenting rejection.
The teachings of the co-pending claims in view of Jentzer and Kauffmann have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the DPP3 inhibitor is administered in combination with an angiotensin receptor agonist recited in the claims including angiotensin I, II, III, IV and analogues thereof.
However, Chawla teaches that angiotensinogen, Angiotensin I, Angiotensin II, angiotensin III, and angiotensin IV are hormones naturally produced by the body that regulate blood pressure via vasoconstriction and sodium reabsorption (Para. 0005) and thus discloses methods of treating hypotension (such as catecholamine-resistant hypertension) in a patient comprising administering an angiotensin therapeutic agent such as angiotensin I, angiotensin II, angiotensin III, angiotensin IV, or analogues thereof (Para. 0006-0007), wherein the patient has cardiogenic, distributive, or septic shock (Para. 0047). The angiotensin II is preferably 5-L-isoleucine angiotensin II (or human angiotensin II) having the sequence set forth in SEQ ID NO: (DRVYIHPF) corresponding to SEQ ID NO: 13 (DRVYIHPF) (Para. 0039 and 0068). Angiotensin II analogues contemplated for use include 5-L-valine angiotensin II [SEQ ID NO: 2, DRVYVHPF)] corresponding to SEQ ID NO: 14 (DRVYVHPF) of the instant claims; [Asn1-Phe4-]-angiotensin II [SEQ ID NO: 3 (NRVFIHPF)] corresponding to SEQ ID NO: 15 (NRVFIHPF) of the instant claims; angiotensin II nonapeptide [SEQ ID NO: 4 (NRVYYVHPF)] corresponding to SEQ ID NO: 17 (NRVYYVHPF) of the instant claims; [Asn1-Ile5-Ile8]-angiotensin II [SEQ ID NO:5 (NRVYIHPI)] corresponding to SEQ ID NO: SEQ ID NO: 18 (NRVYIHPI) of the instant claims; [Asn1-Ile5-Ala8]-angiotensin II [SEQ ID NO:6 (NRVYIHPA)] corresponding to SEQ ID NO: 19 (NRVYIHPA) of the instant claims; and [Asn1-diiodoTyr4-Ile5]-angiotensin II [SEQ ID NO:7 (NRVYIHPF)] corresponding to SEQ ID NO: 20 (NRVYIHPF) of the instant claims (Para. 0039 and 0068). The angiotensin III preferably has the sequence set forth in SEQ ID NO: 8 (or human angiotensin III) (RVYIHPF) corresponding to SEQ ID NO: (RVYIHPF) of the instant claims. The angiotensin III analogues also contemplated for use include 4-valine angiotensin III [SEQ ID NO: 9 (RVYVHPF)] corresponding to SEQ ID NO: 22 (RVYVHPF) of the instant claims; [Phe3]-angiotensin III [SEQ ID NO:10 (RVFIHPF)] corresponding to SEQ ID NO: 23 of the instant claims; [Ile4-Ala7]-angiotensin III [SEQ ID NO:11 (RVYIHPA) corresponding to SEQ ID NO: 24 of the instant claims (RVYIHPA); and [diiodoTyr3-Ile4]-angiotensin III [SEQ ID NO:12 (RVYIHPF)] corresponding to SEQ ID NO: 25 of the instant claims (Para. 0040 and Para. 0070). The angiotensin IV preferably has the sequence set forth in SEQ ID NO: 13 (or human angiotensin IV) (VYIHPF) corresponding to both SEQ ID NO: 16 (angiotensin II hexapeptide - VYIHPF) and SEQ ID NO: 26 (VYIHPF) of the instant claims. The angiotensin IV analogues contemplated for use include Val3 -angiotensin IV [SEQ ID NO: 14 (VYVHPF)] corresponding to SEQ ID NO: 27 (VYVHPF) of the instant claims; [Phe2]-angiotensin IV [SEQ ID NO:15 (VFIHPF)] corresponding to SEQ ID NO: 28 (VFIHPF) of the instant claims; [Ile3-Ala6]-angiotensin IV [SEQ ID NO:16 (VYIHPA)] corresponding to SEQ ID NO: 29 (VYIHPA) of the instant claims; and [diiodoTyr2-Ile3]-angiotensin IV [SEQ ID NO:17 (VYIHPF)] corresponding to SEQ ID NO: 30 (VYIHPF) of the instant claims (Para. 0041 and Para. 0072) (see also Examples of Sequences on Pages 91-92 of the instant specification).
It would have been obvious to one of ordinary skill in the art to modify the method of the co-pending claims such that administer an angiotensin receptor agonist such as angiotensin I, II, III, IV, or an analogue thereof in combination with an inhibitor of DPP3 activity to a subject having an elevated DPP3 level relative to a predetermined threshold, a characteristic of necrotic-related processes such as cardiogenic and septic shock. One of ordinary skill in the art would have been motivated to do so since angiotensin I, II, III, IV and analogues thereof regulate blood pressure via vasoconstriction and sodium reabsorption and thus can be used to effectively treat hypotension in patients suffering from various forms of shock (e.g. cardiogenic, distributive, or septic shock) in patients, including hypotension that is resistant (or refractory) to other treatment modalities (e.g. catecholamines) as taught by Chawla. Therefore, one of ordinary skill in the art would reasonably expect that administering angiotensin I, II, III, IV or an analogue thereof angiotensin II in combination with an DPP3 activity inhibitor to effectively treat a shock in a subject having elevated DPP3 levels relative to a predetermined threshold.
Claims 22 and 36-43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-26 copending Application No. 18998052 (reference application) in view of Jentzer, Kauffman, and Chawla as applied to claims 18, 19, 18, 26-35, and 44 above, and further in view of Xu et al (Xu, Tu, et al. "Flexible combination of multiple diagnostic biomarkers to improve diagnostic accuracy." BMC medical research methodology 15.1 (2015): 94, of record), hereinafter Xu, Morgenthaler et al (EP1619505B1, of record), hereinafter Morgenthaler, and Struck et al (WO2019077082A1), hereinafter Struck.
This is a provisional nonstatutory double patenting rejection.
The teachings of co-pending claims in view of Jentzer, Kauffmann, and Chawla have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the level of pro-adrenomedullin or fragments thereof in a sample of plasma is also determined and treatment with an anti-ADM antibody or fragment thereof is initiated when the level is above a predetermined threshold or treatment with the anti-ADM antibody is withheld/terminated if the determined level of pro-adrenomedullin or fragments thereof is below said predetermined threshold, wherein the anti-ADM antibody has the CDRs recited in the instant claims and the predetermined threshold level of pro-ADM comprises ADM-NH2 in a range of 50 pg/ml – 250 pg/mL/ MR-proADM in a range of 0.5 nmol/L and 3 nmol/L; or CT-proADM in a range of 85 pmol/L – 500 pmol/L.
However, Xu teaches that diagnosis based on multiple biomarkers assessed in an individual rather a single biomarker improves diagnostic accuracy (Abstract and 3rd paragraph under Introduction).
Morgenthaler further teaches determining the concentration of pro-adrenomedullin (pro-ADM) or physiologically occurring fragments thereof in a body fluid sample from a critically ill patient to identify a life-threatening crisis requiring intervention, including sepsis and septic shock, and to assess mortality risk in diseases such as sepsis and septic shock (Abstract, Para. 0002, 0003, 0025, and 0028–0031). Further disclosed are specific cut-off values for interpreting such measurements in septic ICU patients where values above 8 nmol/L identify patients that have greatly increased mortality risk (para. 0042–0044). When pro-ADM levels are critically high, therapeutic intervention is warranted via administration of adrenomedullin antagonists such as antibodies that bind ADM and block its receptor interaction (e.g. antibodies to adrenomedullin that block its receptor binding sites: “immunological neutralization”) to treat conditions such as septic shock (para. 0055–0057, 0060, and 0066). Accordingly, Morgenthaler describes measuring pro-ADM in shock patients, comparing the level to a disclosed threshold, and initiating treatment with an anti-ADM antibody when the level exceeds that threshold.
Struck further teaches the anti-ADM antibody HAM8101 (adrecizumab) for use in treating subjects suffering from shock (e.g. sepsis/septic shock), wherein HAM8101 comprises the heavy chain of SEQ ID NO: 26 and the light chain of SEQ ID NO: 27 (Page 6, Ln. 26-31 to Page 7, Ln. 1-2; Page 7, Ln. 13-15; Page 19, Ln. 4-6; Page 13, Ln. 15-32; Example 1, Page 44). The heavy chain of adrecizumab fully comprises the CDRs of SEQ ID NOs: 38-40 and the VH chain of SEQ ID NO: 44 recited in the instant claims. The light chain of adrecizumab fully comprises the CDRs of SEQ ID NO: 41, RVS, SEQ ID NO: 42 of the instant claims. HAM8101 is identified as adrecizumab and thus has all of the sequences recited in the instant claims (see “Examples of Seqeunces on Page 94 of instant specification). Further disclosed is the determination of specific proADM-derived biomarkers including MR-proADM and CT-proADM (Page 6). Elevated levels of these pro-ADM fragments above a certain threshold are described as correlating with enhanced risk of adverse outcome (Page 28, Ln. 4-11). For plasma MR-proADM, the threshold is between 0.5 to 1.5 nmol/L, preferably 0.7 to 1 nmol/L, and most preferably is 0.8 nmol/L (Page 27, Ln. 1-3). For plasma CT-proADM, the threshold is between 85 to 350 pmol/L, preferably between 100 to 200 pmol/L, and most preferably is 150 pmol/L (Page 27, Ln. 5-7). Additionally, healthy-subject reference values for plasma mature ADM-NH2 (or bio-ADM) levels are also taught, including a median value of about 24.7 pg/mL, a lowest value of about 11 pg/ml and a 99th percentile value at about 43 pg/ml (Page 30, Ln. 25-29). These disclosed reference values can thus be used to distinguish healthy subjects from subjects having elevated ADM-NH2 levels associated with disease and/or shock states via routine optimization. MR-proADM has the amino acid sequence of SEQ ID NO: 4 (ELRMSS SYPTGLADVK AGPAQTLIRP QDMKGASRSP EDSSPDAARI RV) corresponding to SEQ ID NO: 33 (ELRMSS SYPTGLADVK AGPAQTLIRP QDMKGASRSP EDSSPDAARI RV) of the instant claims (see “Examples of Sequences” on Page 30 of instant specification and Sequence Listing on Page 52 of Struck). CT-proADM has the amino acid sequence of SEQ ID NO: 5 (RRR RRSLPEAGPG RTLVSSKPQA HGAPAPPSGS APHFL) corresponding to SEQ ID NO: 36 (RRR RRSLPEAGPG RTLVSSKPQA HGAPAPPSGS APHFL) of the instant claims (see “Examples of Sequences” on Page 30 of instant specification and Sequence Listing on Page 52 of Struck). Mature ADM (bio-ADM) has the amino acid sequence of SEQ ID NO: 1 (shown below) corresponding to SEQ ID NO: 34 recited in the instant claims (see “Examples of Sequences” on Page 30 of instant specification and Sequence Listing on Page 52 of Struck).
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It would have been obvious to one of ordinary skill in the art to modify the method of the co-pending claims in view of Jentzer, Kauffman, and Chawla such that the levels of pro-ADM or fragments thereof—e.g. ADM-NH2, MR-proADM, or CT-proAMD- in a subject having refractory shock are further determined and anti-ADM antibody therapy is initiated if the levels are above a predetermined threshold. One of ordinary skill in the art would have been motivated to do so since Xu suggests that assessing multiple biomarkers rather than a single biomarker helps improve diagnostic accuracy, and Morgenthaler provides guidance for using pro-ADM and/or fragments thereof to diagnose and treat shock with anti-ADM antibody therapy. In particular, Struck identifies the anti-ADM antibody HAM8101 for use in treating subjects having shock and further teaches determination of specific pro-ADM fragments including MR-proADM and CT-proADM to identify subjects having increased risk of outcome. Additionally, Struck teaches measurement of mature ADM-NH2 (bio-ADM) and disclosed healthy-subject reference values useful for distinguishing healthy vs diseased subjects via routine optimization. Indeed, the courts have stated that [W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); thus it would have been prima facie obvious to one of ordinary skill in the art to determine by routine experimentation the optimum threshold values of ADM-NH2, MR-proADM, or CT-proADM levels to arrive at the specific embodiments recited in the claims for identifying patients that would benefit from anti-ADM antibody therapy. Therefore, one of ordinary skill in the art would reasonably expect that further determining the levels of pro-ADM or fragments thereof (e.g. ADM-NH2, MR-proADM, or CT-proADM) in a refractory shock patient and initiating anti-ADM antibody therapy when those levels are above a predetermined threshold can effectively treat refractory shock in said patient.
Claims 18, 26-31, and 44 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of U.S. Patent No. 11530276B2 in view of Bergmann (WO2017182561A1) and Jentzer et al (Jentzer, Jacob C., et al. "Management of refractory vasodilatory shock." Chest 154.2 (2018): 416-426), hereinafter Jentzer.
The issued patent discloses an anti-DPP3 monoclonal antibody having the heavy chain CDRs of SEQ ID NOs: 7-9 and the light chain CDRs of SEQ ID NO: 10, KVS, and SEQ ID NO: 11 (or the heavy chain of SEQ ID NO: 12 corresponding to SEQ ID NO: 11 of the instant claims and the light chain of SEQ ID NO: 13 corresponding to SEQ ID NO: 12 of the instant claims) (issued claims 1 and 6). The light chain of SEQ ID NO: 13 fully comprises the VL chain of SEQ ID NO: 4 and the light chain CDRs of SEQ ID NO: 10, KVS, and SEQ ID NO: 11 recited in instant claims. The anti-DPP3 antibody recited in both the co-pending and instant claims is clone AK1967, and thus the anti-DPP3 antibody of the co-pending claims have the CDRs and variable sequences recited in the instant claims (see Sequence Listing on Column 57 of issued specification as well as “Examples of Sequences” on Pages 89-91 of the instant specification). Per the issued specification, the anti-DPP3 antibody of recited in the issued claims is clone AK1967, which can inhibit the activity of DPP3 (see Examples 1-3, Columns 45-51; Sequence Listing, Column 57).
The issued claims do not teach a method of treating shock in a subject comprising administering the anti-DPP3 monoclonal antibody AK1967 (a DPP3 inhibitor) to a subject having a level of DPP3 in a sample of body fluid above a predetermined threshold, wherein said subject has refractory shock.
However, Bergmann discloses a method for treating a disease or condition associated with necrotic processes in a subject comprising administering an inhibitor of DPP3 activity to the subject, wherein the subject has an elevated level of DPP3 above a predetermined threshold level (Page 39, Ln. 13-15; Page 40, Ln. 22-25). While it is not explicitly stated that cardiogenic or septic shock are diseases/conditions accompanied by or related to necrotic processes, elevated DPP3 levels relative to a predetermined threshold is a diagnostic criterion for said diseases or conditions. Specifically, it has been shown that patients with cardiogenic or septic shock exhibit elevated DPP3 plasma levels compared to healthy controls (Example 1). Thus, elevated DPP3 levels relative to a predetermined threshold can be used to identify a subject with shock states (e.g. cardiogenic or septic shock) that can be treated with a DPP3 activity inhibitor. The DPP3 activity inhibitor is, in some embodiments, an anti-DPP3 antibody or fragment thereof (Page, 36, Ln. 4-18). The threshold is predetermined by measuring DPP3 concentration and/or DPP3 activity in healthy controls and calculating, e.g., the 75th percentile, 90th percentile, or 95th percentile, wherein the upper border of a percentile defines the threshold for healthy versus diseased patients. In relation to said percentiles, the threshold that divides between healthy and diseased patients may be between 5 and 25 ng/ ml in plasma using a sandwich type anti-DPP3 immunoassay (Page 23, Ln. 4-16). It is further stated that a person skilled in the art knows a) how to determine thresholds from conducted previous studies and b) that a specific threshold value may depend on the cohort used for calculating a pre-determined threshold that can be later-on used in routine (Page 23, Ln. 18-24). Thus, the threshold value for DPP3 levels is recognized in the prior art as a result-effective variable to determine healthy vs diseased populations.
Jentzer further teaches that refractory shock is a lethal manifestation of cardiovascular failure defined by an inadequate hemodynamic response to high doses of vasopressor medications. Approximately 7% of critically ill patients will develop refractory shock, with short-term mortality exceeding 50% (Abstract), thus patients with refractory shock represent a patient population in need of therapeutic intervention.
Therefore, it would have been obvious to one of ordinary skill in the art to administer the anti-DPP3 monoclonal antibody AK1967 (a DPP3 inhibitor) of the issued claims to a subject having DPP3 levels in a body fluid sample above a predetermined threshold in order to treat refractory shock in said subject. One of ordinary skill in the art would have been motivated to do so since elevated DPP3 levels are a diagnostic criterion for different forms of shock including cardiogenic and septic shock in a subject, and a DPP3 inhibitor such the anti-DPP3 antibody of the issued claims can be used to treat shock in said subject as taught by Bergmann. Further, refractory shock represents a severe subset of shock requiring therapeutic intervention as taught by Jentzer. Since a DPP3 inhibitor can be used to effectively treat shock, artisans would reasonably expect that patients with refractory shock would likewise receive therapeutic benefit. Lastly, the courts have stated that [W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); thus it would have been prima facie obvious to one of ordinary skill in the art to determine by routine experimentation the optimum threshold values of DPP3 levels to arrive at the specific embodiments recited in the claims for identifying and treating patients having refractory shock. Therefore, one of ordinary skill in the art to administer the anti-DPP3 antibody to treat refractory shock in a subject determined to have DPP3 levels above a predetermined threshold.
Claims 19 and 32-35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of U.S. Patent No. 11530276B2 in view of Bergmann and Jentzer, as applied to claims 18, 26-31, and 44 above, and further in view of Chawla (US20170196931A1).
The teachings of the issued claims in view of Bergmann and Jentzer have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the DPP3 inhibitor is administered in combination with an angiotensin receptor agonist recited in the claims including angiotensin I, II, III, IV and analogues thereof.
However, Chawla teaches that angiotensinogen, Angiotensin I, Angiotensin II, angiotensin III, and angiotensin IV are hormones naturally produced by the body that regulate blood pressure via vasoconstriction and sodium reabsorption (Para. 0005) and thus discloses methods of treating hypotension (such as catecholamine-resistant hypertension) in a patient comprising administering an angiotensin therapeutic agent such as angiotensin I, angiotensin II, angiotensin III, angiotensin IV, or analogues thereof (Para. 0006-0007), wherein the patient has cardiogenic, distributive, or septic shock (Para. 0047). The angiotensin II is preferably 5-L-isoleucine angiotensin II (or human angiotensin II) having the sequence set forth in SEQ ID NO: (DRVYIHPF) corresponding to SEQ ID NO: 13 (DRVYIHPF) (Para. 0039 and 0068). Angiotensin II analogues contemplated for use include 5-L-valine angiotensin II [SEQ ID NO: 2, DRVYVHPF)] corresponding to SEQ ID NO: 14 (DRVYVHPF) of the instant claims; [Asn1-Phe4-]-angiotensin II [SEQ ID NO: 3 (NRVFIHPF)] corresponding to SEQ ID NO: 15 (NRVFIHPF) of the instant claims; angiotensin II nonapeptide [SEQ ID NO: 4 (NRVYYVHPF)] corresponding to SEQ ID NO: 17 (NRVYYVHPF) of the instant claims; [Asn1-Ile5-Ile8]-angiotensin II [SEQ ID NO:5 (NRVYIHPI)] corresponding to SEQ ID NO: SEQ ID NO: 18 (NRVYIHPI) of the instant claims; [Asn1-Ile5-Ala8]-angiotensin II [SEQ ID NO:6 (NRVYIHPA)] corresponding to SEQ ID NO: 19 (NRVYIHPA) of the instant claims; and [Asn1-diiodoTyr4-Ile5]-angiotensin II [SEQ ID NO:7 (NRVYIHPF)] corresponding to SEQ ID NO: 20 (NRVYIHPF) of the instant claims (Para. 0039 and 0068). The angiotensin III preferably has the sequence set forth in SEQ ID NO: 8 (or human angiotensin III) (RVYIHPF) corresponding to SEQ ID NO: (RVYIHPF) of the instant claims. The angiotensin III analogues also contemplated for use include 4-valine angiotensin III [SEQ ID NO: 9 (RVYVHPF)] corresponding to SEQ ID NO: 22 (RVYVHPF) of the instant claims; [Phe3]-angiotensin III [SEQ ID NO:10 (RVFIHPF)] corresponding to SEQ ID NO: 23 of the instant claims; [Ile4-Ala7]-angiotensin III [SEQ ID NO:11 (RVYIHPA) corresponding to SEQ ID NO: 24 of the instant claims (RVYIHPA); and [diiodoTyr3-Ile4]-angiotensin III [SEQ ID NO:12 (RVYIHPF)] corresponding to SEQ ID NO: 25 of the instant claims (Para. 0040 and Para. 0070). The angiotensin IV preferably has the sequence set forth in SEQ ID NO: 13 (or human angiotensin IV) (VYIHPF) corresponding to both SEQ ID NO: 16 (angiotensin II hexapeptide - VYIHPF) and SEQ ID NO: 26 (VYIHPF) of the instant claims. The angiotensin IV analogues contemplated for use include Val3 -angiotensin IV [SEQ ID NO: 14 (VYVHPF)] corresponding to SEQ ID NO: 27 (VYVHPF) of the instant claims; [Phe2]-angiotensin IV [SEQ ID NO:15 (VFIHPF)] corresponding to SEQ ID NO: 28 (VFIHPF) of the instant claims; [Ile3-Ala6]-angiotensin IV [SEQ ID NO:16 (VYIHPA)] corresponding to SEQ ID NO: 29 (VYIHPA) of the instant claims; and [diiodoTyr2-Ile3]-angiotensin IV [SEQ ID NO:17 (VYIHPF)] corresponding to SEQ ID NO: 30 (VYIHPF) of the instant claims (Para. 0041 and Para. 0072) (see also Examples of Sequences on Pages 91-92 of the instant specification).
It would have been obvious to one of ordinary skill in the art to modify the method of the issued claims such that administer an angiotensin receptor agonist such as angiotensin I, II, III, IV, or an analogue thereof in combination with an inhibitor of DPP3 activity to a subject having an elevated DPP3 level relative to a predetermined threshold, a characteristic of necrotic-related processes such as cardiogenic and septic shock. One of ordinary skill in the art would have been motivated to do so since angiotensin I, II, III, IV and analogues thereof regulate blood pressure via vasoconstriction and sodium reabsorption and thus can be used to effectively treat hypotension in patients suffering from various forms of shock (e.g. cardiogenic, distributive, or septic shock) in patients, including hypotension that is resistant (or refractory) to other treatment modalities (e.g. catecholamines) as taught by Chawla. Therefore, one of ordinary skill in the art would reasonably expect that administering angiotensin I, II, III, IV or an analogue thereof angiotensin II in combination with an DPP3 activity inhibitor to effectively treat a shock in a subject having elevated DPP3 levels relative to a predetermined threshold.
Claims 22 and 36-43 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of U.S. Patent No. 11530276B2 in view of Bergmann, Jentzer, and Chawla, as applied to claims 18, 19, 18, 26-35, and 44 above, and further in view of Xu et al (Xu, Tu, et al. "Flexible combination of multiple diagnostic biomarkers to improve diagnostic accuracy." BMC medical research methodology 15.1 (2015): 94, of record), hereinafter Xu, Morgenthaler et al (EP1619505B1, of record), hereinafter Morgenthaler, and Struck et al (WO2019077082A1), hereinafter Struck.
The teachings of issued claims in view of Bergmann, Jentzer, and Chawla have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the level of pro-adrenomedullin or fragments thereof in a sample of plasma is also determined and treatment with an anti-ADM antibody or fragment thereof is initiated when the level is above a predetermined threshold or treatment with the anti-ADM antibody is withheld/terminated if the determined level of pro-adrenomedullin or fragments thereof is below said predetermined threshold, wherein the anti-ADM antibody has the CDRs recited in the instant claims and the predetermined threshold level of pro-ADM comprises ADM-NH2 in a range of 50 pg/ml – 250 pg/mL/ MR-proADM in a range of 0.5 nmol/L and 3 nmol/L; or CT-proADM in a range of 85 pmol/L – 500 pmol/L.
However, Xu teaches that diagnosis based on multiple biomarkers assessed in an individual rather a single biomarker improves diagnostic accuracy (Abstract and 3rd paragraph under Introduction).
Morgenthaler further teaches determining the concentration of pro-adrenomedullin (pro-ADM) or physiologically occurring fragments thereof in a body fluid sample from a critically ill patient to identify a life-threatening crisis requiring intervention, including sepsis and septic shock, and to assess mortality risk in diseases such as sepsis and septic shock (Abstract, Para. 0002, 0003, 0025, and 0028–0031). Further disclosed are specific cut-off values for interpreting such measurements in septic ICU patients where values above 8 nmol/L identify patients that have greatly increased mortality risk (para. 0042–0044). When pro-ADM levels are critically high, therapeutic intervention is warranted via administration of adrenomedullin antagonists such as antibodies that bind ADM and block its receptor interaction (e.g. antibodies to adrenomedullin that block its receptor binding sites: “immunological neutralization”) to treat conditions such as septic shock (para. 0055–0057, 0060, and 0066). Accordingly, Morgenthaler describes measuring pro-ADM in shock patients, comparing the level to a disclosed threshold, and initiating treatment with an anti-ADM antibody when the level exceeds that threshold.
Struck further teaches the anti-ADM antibody HAM8101 (adrecizumab) for use in treating subjects suffering from shock (e.g. sepsis/septic shock), wherein HAM8101 comprises the heavy chain of SEQ ID NO: 26 and the light chain of SEQ ID NO: 27 (Page 6, Ln. 26-31 to Page 7, Ln. 1-2; Page 7, Ln. 13-15; Page 19, Ln. 4-6; Page 13, Ln. 15-32; Example 1, Page 44). The heavy chain of adrecizumab fully comprises the CDRs of SEQ ID NOs: 38-40 and the VH chain of SEQ ID NO: 44 recited in the instant claims. The light chain of adrecizumab fully comprises the CDRs of SEQ ID NO: 41, RVS, SEQ ID NO: 42 of the instant claims. HAM8101 is identified as adrecizumab and thus has all of the sequences recited in the instant claims (see “Examples of Seqeunces on Page 94 of instant specification). Further disclosed is the determination of specific proADM-derived biomarkers including MR-proADM and CT-proADM (Page 6). Elevated levels of these pro-ADM fragments above a certain threshold are described as correlating with enhanced risk of adverse outcome (Page 28, Ln. 4-11). For plasma MR-proADM, the threshold is between 0.5 to 1.5 nmol/L, preferably 0.7 to 1 nmol/L, and most preferably is 0.8 nmol/L (Page 27, Ln. 1-3). For plasma CT-proADM, the threshold is between 85 to 350 pmol/L, preferably between 100 to 200 pmol/L, and most preferably is 150 pmol/L (Page 27, Ln. 5-7). Additionally, healthy-subject reference values for plasma mature ADM-NH2 (or bio-ADM) levels are also taught, including a median value of about 24.7 pg/mL, a lowest value of about 11 pg/ml and a 99th percentile value at about 43 pg/ml (Page 30, Ln. 25-29). These disclosed reference values can thus be used to distinguish healthy subjects from subjects having elevated ADM-NH2 levels associated with disease and/or shock states via routine optimization. MR-proADM has the amino acid sequence of SEQ ID NO: 4 (ELRMSS SYPTGLADVK AGPAQTLIRP QDMKGASRSP EDSSPDAARI RV) corresponding to SEQ ID NO: 33 (ELRMSS SYPTGLADVK AGPAQTLIRP QDMKGASRSP EDSSPDAARI RV) of the instant claims (see “Examples of Sequences” on Page 30 of instant specification and Sequence Listing on Page 52 of Struck). CT-proADM has the amino acid sequence of SEQ ID NO: 5 (RRR RRSLPEAGPG RTLVSSKPQA HGAPAPPSGS APHFL) corresponding to SEQ ID NO: 36 (RRR RRSLPEAGPG RTLVSSKPQA HGAPAPPSGS APHFL) of the instant claims (see “Examples of Sequences” on Page 30 of instant specification and Sequence Listing on Page 52 of Struck). Mature ADM (bio-ADM) has the amino acid sequence of SEQ ID NO: 1 (shown below) corresponding to SEQ ID NO: 34 recited in the instant claims (see “Examples of Sequences” on Page 30 of instant specification and Sequence Listing on Page 52 of Struck).
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It would have been obvious to one of ordinary skill in the art to modify the method of the issued claims in view of Bergman, Jentzer, and Chawla such that the levels of pro-ADM or fragments thereof—e.g. ADM-NH2, MR-proADM, or CT-proAMD- in a subject having refractory shock are further determined and anti-ADM antibody therapy is initiated if the levels are above a predetermined threshold. One of ordinary skill in the art would have been motivated to do so since Xu suggests that assessing multiple biomarkers rather than a single biomarker helps improve diagnostic accuracy, and Morgenthaler provides guidance for using pro-ADM and/or fragments thereof to diagnose and treat shock with anti-ADM antibody therapy. In particular, Struck identifies the anti-ADM antibody HAM8101 for use in treating subjects having shock and further teaches determination of specific pro-ADM fragments including MR-proADM and CT-proADM to identify subjects having increased risk of outcome. Additionally, Struck teaches measurement of mature ADM-NH2 (bio-ADM) and disclosed healthy-subject reference values useful for distinguishing healthy vs diseased subjects via routine optimization. Indeed, the courts have stated that [W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); thus it would have been prima facie obvious to one of ordinary skill in the art to determine by routine experimentation the optimum threshold values of ADM-NH2, MR-proADM, or CT-proADM levels to arrive at the specific embodiments recited in the claims for identifying patients that would benefit from anti-ADM antibody therapy. Therefore, one of ordinary skill in the art would reasonably expect that further determining the levels of pro-ADM or fragments thereof (e.g. ADM-NH2, MR-proADM, or CT-proADM) in a refractory shock patient and initiating anti-ADM antibody therapy when those levels are above a predetermined threshold can effectively treat refractory shock in said patient.
Response to Arguments
Applicant's arguments filed 02/20/2026 have been fully considered but they are not persuasive.
With respect to rejections made under 35 USC 112(a) written description, Applicant argues that after reviewing Janeway et al, a person of ordinary skill in the art would understand that the anti-ADM antibodies or antibody fragments of the amended claim 22 may not necessarily make contact with all of the CDRs because, according to Janeway “hypervariable loops (complementarity-determining regions)” may “determine the specificity of antibodies”. Thus, Applicant contends that while the antigen has six CDRs, that is not to say that all six CDRs are necessarily involved with binding. Applicant further points out that Janeway says “[p]eptides binding to antibodies usually bind in the cleft between the V regions of the heavy and light chains, where they make specific contact with some, but not necessarily all, of the hypervariable loops,” and that “[t]his is also the usual mode of binding for carbohydrate antigens and small molecules such as haptens”. Thus, Applicant asserts that in accordance to Janeway, not necessarily all six non-degenerate CDRs for the gens of anti-ADM antibodies or antibody fragments are necessary to treat refractory shock in a subject, given that ADM is a small peptide.
In response to Applicant’s arguments, the Examiner notes that Applicant’s summary of Janeway provides a mischaracterization of the teachings of Janeway.
While Applicant cherry-picks language allegedly suggesting that hypervariable regions “may” determine antibody specificity, Janeway as a whole teaches that the hypervariable regions [i.e. the complementarity determining regions (CDRs)] are responsible for antigen binding specificity. The first selection pointed out by Applicant is presented in full below:
“X-ray crystallographic analysis of antigen:antibody complexes has demonstrated that the hypervariable loops (complementarity-determining regions) of immunoglobulin V regions determine the specificity of antibodies.”
As written, this selection in no way casts doubt on the role hypervariable regions play in antibody recognition as Applicant appears to suggest. Indeed, the CDR3 sequences from the heavy and light chains alone are not sufficient to define antibody binding to a specific target and functional outcome. For example, the same HCDR3 can be generated from different V(D)J rearrangements, but target binding depends on the specific VH/VL context and pairing; thus HCDR3 alone is insufficient for defining antibody specificity. Notably, in unselected libraries, most antibodies sharing an identical HCDR3 fail to bind the target (CDK2), highlighting the importance of the surrounding sequence and structural context (D’Angelo et al, Abstract and Page 8, right column). Without further guidance, artisans would necessarily have to engage in additional research (e.g. screening and testing) to identify the full scope of inhibitors that block DPP3 activity and treat shock in a subject. Therefore, defining the CDR3 regions alone of an inhibitory DPP3 antibody or anti-ADM antibody is insufficient, and all six CDR sequences having the functional properties set forth in the claims must also be identified.
Further, the statement that a peptide antigen may not “necessarily” contact all CDRs is not a definitive rule for all peptide antigens. Even if, for the sake of argument, it is assumed that certain peptides may not physically contact every CDR, Applicant has provided no evidence demonstrating that the claimed anti-ADM antibody does not require six CDRs for specifically binding to ADM and treating refractory shock in a subject. Arguments presented by applicant cannot take the place of evidence in the record. See In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984); In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) (“An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness.”). (MPEP 2145). Therefore, the 35 USC 112a written description rejection is maintained.
With respect to the rejection made under 35 USC 112(b), Applicant argues that the amendments to claim 22 obviates the rejection. However, as discussed above, claim 22, as amended, recites that treatment with an anti-ADM antibody is initiated when pro-ADM levels are above a predetermined threshold. Alternatively, the initiated treatment is withheld and/or terminated if the pro-ADM levels are below a predetermined threshold. As presently written, step 1 of the method is measuring pro-ADM levels. Step 2 is either a) initiating treatment when pro-ADM levels are above a threshold OR b) terminating the initiated treatment when pro-ADM levels are below a threshold. The only recited measurement of pro-ADM levels occurs prior to treatment initiation. The alternative limitation requires an already initiated treatment to be terminated based on biomarker levels below a threshold. However, no subsequent measuring step after initiating treatment is recited to provide a basis for withholding or terminating treatment later. Therefore, claim 22 does not clearly set forth the metes and bounds of the patent prosecution desired. Claims 36-42, which depend directly or indirectly from claim 22, do not cure the deficiencies of claim 22 and are thus also rejected. Therefore, the 35 USC 112(b) rejection over claim 22 is maintained.
With respect to rejections made under 35 USC 103, Applicant argues that it would not have been obvious to treat a subject having refractory shock and that the primary reference Bergmann does not teach this subset of patients. Further, Applicant argues that the specific predetermined threshold values set forth in the amended claims are not taught. Additionally, Applicant argues that the secondary references do not cure the deficiencies of the primary reference.
In response to Applicant’s arguments, the Examiner notes that previously the claims recited a method for predicting is a subject ran into refractory shock by determining if DPP3 levels were above a predetermined threshold. As such, the claims previously defined a subject having refractory shock if there were elevated DPP3 levels above some generic threshold. Thus, Bergmann which teaches identification of subjects having shock by determining level of DPP3 over some threshold met that limitation. As presently amended, the claim recites a method of treating refractory shock. In view of these claim amendments, the Examiner notes that Jentzer teaches that refractory shock represents a severe subset of shock requiring therapeutic intervention Since a DPP3 inhibitor can be used to effectively treat shock, artisans would reasonably expect that patients with refractory shock would likewise receive therapeutic benefit. Further, the courts have stated that [W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); thus it would have been prima facie obvious to one of ordinary skill in the art to determine by routine experimentation the optimum threshold values of DPP3 levels to arrive at the specific embodiments recited in the claims for identifying and treating patients having refractory shock. Therefore, the 35 USC 103 rejections are maintained.
With respect to rejections made under double patenting, Applicant sets forth similar arguments regarding the prior art rejections. As such, the double patenting rejections are maintained for the reasons discussed above.
Conclusion
No claims are allowable.
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.
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/LIA E TAYLOR/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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