DETAILED ACTION
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 .
Priority
The instant application is a domestic application filed on 06/21/2024, which claims the benefit of U.S. Provisional Patent Application No. 63/522,823, filed on 06/23/2023.
Status of Claims
Claims 1-15 were originally presented on 06/21/2024 and are pending.
Information Disclosure Statement
Two separate Information Disclosure Statements (“IDSs”) have been submitted, one on 09/24/2024, and one on 09/24/2024. The IDSs are in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDSs have been considered by the examiner.
Claim Objections
Claim 4 objected to because of the following informalities:
The chemical structure depicted of the API administered (macitentan) is blurry.
Appropriate correction is required.
Drawings and Specification
On 06/21/2024, the Office received Applicant’s petition for the Office to accept color drawings for Figures 1, 11, 15, 20, and 22. On 08/09/2024, the Office granted Applicant’s petition. The examiner reviewed the color drawings and finds that no new matter is introduced by inclusion of such drawings. The Specification at 3, paragraph [0014], states the language as required under 37 C.F.R. 1.84 to indicate that color drawings were filed. The drawings are therefore accepted.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-15 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.
Claims 1-15 Indefinite – Unclear which Species/Actives are Administered
Regarding claim 1, it recites a method of treatment comprising administering the active “an endothelin receptor inhibitor”. The claim term “an endothelin receptor inhibitor” represents vague functional language that is not defined precisely in the specification. Further, one of skill in the art could not envision all of the administered actives encompassed by the claims due to the vague language. As a result, and it is unclear which actives are intended to be administered in the claims, in part due to there being more than one reasonable interpretation of which species/actives are administered in the claims. In particular, it is unclear the administration of which actives Applicant regards as the invention.
The plain an ordinary meaning of “an endothelin receptor inhibitor” is an “inhibitor” of “an endothelin receptor”. There are multiple endothelins (e.g., ET-1, 2, or 3), endothelin receptors (e.g., ETA, ETB1, ETB2, etc.), and such receptors are expressed by different genes in different species of animals. See, e.g., Hyndman 20091 at Abstract, and at 680, Fig. 1 (depicting certain phylogeny of different endothelin receptors in different animals, such as humans, dogs, fish, and frogs). Further, “an endothelin receptor inhibitor” is a known class of small compound APIs, such as the API exemplified in the specification, macitentan.
However, in attempt to ascertain a meaning for this claim term, the specification at 7, paragraph [0054] states:
The term “endothelin receptor inhibitor” can refer to any agent that blocks and/or inhibits the binding of endothelin to an endothelin receptor, and/or any agent that blocks or inhibits endothelin receptor-mediated signal transduction. For example, the endothelin receptor inhibitor can comprise an integrin alpha9 (ITGA9) inhibitor.
Specification at 7, paragraph [0054] (emphasis added).
Accordingly, by using the word “can”, the specification sets forth preferences for the actives, rather than precise definitions. Indeed, the actives encompass “any agent” that “blocks and/or inhibits the binding of endothelin to an endothelin receptor” and/or that “blocks or inhibits endothelin receptor-mediated signal transduction”. The preceding paragraph (Specification at 7, paragraph [0053]) gives examples of agents/inhibitors, that “encompass numerous classes of chemical molecules, e.g., small organic or inorganic molecules, polysaccharides, biological macromolecules, e.g., peptides, proteins, peptide analogs and derivatives, peptidomimetics, antibodies, antibody fragments, nucleic acids, nucleic acid analogs and derivatives, an extract made from biological materials such as bacteria, plants, fungi, or animal cells or tissues, naturally occurring or synthetic compositions.” Specification at 7, paragraph [0053].
Nowhere in the specification does Applicant set forth any qualitative metric requirement for “any agent” to “block and/or inhibit” some endothelin interaction with any threshold level of inhibition, nor provide certain tests to rule out “any agent” which “encompass numerous classes of chemical molecules” from any other chemical/active administered to a patient/subject presently having, prone to having, or that had a venous thromboembolic event.
Further, the claim language reads on the administration of “any agent” such as a New Chemical Entity yet to be synthesized and/or discovered that may “block and/or inhibit” some endothelin interaction, or an existing API that inherently possesses some latent property yet to be discovered (binding α9B1, discussed below), which renders the scope of the actives administered indeterminate. This problem is highlighted with certainty with respect to claims 2-4, wherein the “any agent” that may “block and/or inhibit” some endothelin interaction is defined by more vague functional language (“an integrin alpha9 (ITGA9) inhibitor”) (claim 2), that is a small molecule (claim 3), that is macitentan (depicted compound shown in claim 4).
While macitentan is a known small molecule endothelin receptor antagonist, and therefore one would reasonably ascertain the scope of claim 1 encompassing administration of macitentan, prior to Applicant’s disclosure, macitentan was not a known ITGA9 inhibitor. Instead, Applicant performed computer modeling and determined that macitentan docks into a binding site of α9B1. See, e.g., Specification at 28, paragraphs [00143]-[00146]. Accordingly, a way of being “any agent” that may “block and/or inhibit” some endothelin interaction (and thus, be “an endothelin receptor inhibitor”) might include an ex post discovery that an existing API, such as an NSAID like ibuprofen (Advil), which is not classically considered an “endothelin receptor inhibitor”, docks into a binding site of α9B1 following a computer modeling study. Even then, if one were to discover that an NSAID like ibuprofen docks into a binding site of α9B1 following a computer modeling study, there is no threshold qualitative metric requirement for such actual in vitro binding to qualify as an actual “inhibitor” in the context of these claims.
Moreover, claim 4 also recites “a derivative or analog thereof” with respect to macitentan. The claim term “a derivative or analog thereof” is vague, is not defined in the specification, and as a result, it is further unclear which actives are administered in the claim. The administration of all of these derivatives and analogs thereof are encompassed by the parent claim 1.
While claim 4 is precisely defined with respect to the administration of macitentan, “a derivative or analog” of macitentan may encompass any molecule. There are an infinite number of ways one of skill in the art could make a “derivative of analog” of macitentan, all of which result in entirely distinct chemicals that Applicant does not exemplify in the specification. For example, one of skill in the art could make a proteolysis targeting chimera (PROTAC) embedding macitentan, an antibody-drug conjugate (ADC) embedding macitentan, or distinctly alter macitentan’s core structural features by entirely removing the sulfamide linkage. It is unclear the administration of which of the infinite number of “derivative[s] or analog[s]” of macitentan Applicant regards as the invention, because no “derivative of analog” of macitentan is exemplified in the specification.
As a result, one of skill in the art could not envision all of the actives encompassed by the claims that encompass the administration of “any agent” that may “block and/or inhibit” some endothelin interaction, and it is unclear which actives are administered in the claims. Moreover, as evident from the above discussion, the claim term “an endothelin receptor inhibitor” is subject to more than one reasonable interpretation of which species/actives are administered in the claims (e.g., whether “an endothelin receptor inhibitor” means a classical endothelin receptor antagonist, or whether it simply means any chemical that docks into a binding site of α9B1 based off a computer modeling study). Therefore, the metes and the bounds of the claims are indeterminate, and claims 1-15 are rejected as indefinite.
The examiner suggests that Applicant amend the claim language to precisely name the administration of certain APIs for treating a venous thromboembolic event in a subject that Applicant regards as the invention.
Claim Interpretation
The claims are drawn to methods of treatment. The actives, patient populations, routes of administration, and therapeutic endpoints must be construed to ascertain the scope of the claims. Claim 1 is representative of the claim terms construed. It recites:
A method of preventing, treating, or alleviating a symptom of a venous thromboembolic event in a subject, the method comprising administering to the subject in need thereof an endothelin receptor inhibitor.
Instant claim 1.
The actives : As discussed, the claim term “an endothelin receptor inhibitor” is indefinite. A reasonable interpretation of the claims permit the administration of “any agent” which means any chemical with no threshold set for inhibition of “an endothelin receptor”. This interpretation is not searchable. However, with respect to claim 4, “an endothelin receptor inhibitor” must include macitentan, and thus claim 4 provides an example of “an endothelin receptor inhibitor” within the context of these claims. A working definition of a “derivative of analog” of macitentan includes compounds that have structural similarity with macitentan, and are known endothelin receptor antagonists, such as bosentan and aprocitentan. The examiner interprets analogs to mean a compound which is analogous to macitentan. An analogous compound would be a compound that is of the same class – i.e., a small molecule endothelin receptor antagonist.
Other known examples of small molecule endothelin receptor antagonists include APIs such as ambrisentan, sparsentan, sitaxentan, etc. The claims will be construed as to the administration of a small molecule endothelin receptor antagonist.
The patient populations : The specification does not set forth a specific meaning for the claim term “subject”. See Specification at 18, paragraph [0095], thus all organisms are encompassed by the claims. However, from the tenses of the claim terms “preventing”, “treating”, and “alleviating”, the “subject” may be having, or be prone to having, or may have had “a venous thromboembolic event”.
Regarding “a venous thromboembolic event”, the specification uses the abbreviation “VTE”, which the examiner will adopt when its use is clear, as well as the abbreviations for PE and DVT.
Next, the specification does not set forth a specific definition of a VTE, but instead states that it “can refer to” conditions such as “a blood clot form[ing] in a vein”, “deep vein thrombosis (DVT)”, and “pulmonary embolism (PE).” See Specification at 6, paragraph [0051]. The examiner generally interprets “a blood clot” as a “thrombus”.
Further, the examiner interprets claims drawn to certain conditions, such as DVTs or PEs, combined with the “preventing” arm of the claims, as prophylaxis for certain patient populations predisposed for such conditions. For example, the specification states that “Patients with cancer have a 7 to 28-fold higher risk for venous thromboembolism (VTE) than non-cancer patients.” See Specification at 60, paragraph [00368]. Accordingly, claims drawn to unspecific VTEs include cancer patient populations.
Further, certain patient patent populations are inherently prone to DVTs or PEs or have clinical histories of DVTs or PEs. For example, chronic thromboembolic pulmonary hypertension (“CTEPH”) is a condition caused by a blood clot that does not resolve. See, e.g., Teerapuncharoen 20222 at Abstract and at 283-285 (discussing background on this condition). Therefore, patients with CTEPH have may be having, or be subject to having, and by definition have had at VTE (chronic thromboembolic means that there is a chronic thromboembolism). Further, see, e.g., Teerapuncharoen 2022 at 284, Table 1, listing “Risk factors for [CTEPH]”, wherein the very first risk factor at time of PE diagnosis is “Previous or recurrent PE or DVT”.
Further, see Winter 20173 at entire document (discussing VTE, PE, DVT, and complications); see also, id. at 1531 (“Impaired thrombus resolution is the common denominator behind VTE complications, which are postthrombotic syndrome (PTS) and chronic thromboembolic pulmonary hypertension (CTEPH).… While PTS occurs in up to 50% of patients after symptomatic deep vein thrombosis, only a small and poorly defined number of patients are diagnosed with CTEPH after pulmonary embolism.”) (emphasis added); see also, id. at 1535 (“Due to the controversy as to whether CTEPH occurs as a direct consequence of acute PE, doubts have been raised as to the thromboembolic nature of the disease [71]. However, findings from a prospective international registry reported a history of PE in 74.8%, and a history of DVT in 56.1% of CTEPH patients, thus labeling CTEPH as a chronic complication of VTE [72].”) (emphasis added).
The routes of administration : No specific requirement, but examples of administration through a pharmaceutical composition by any route (e.g., oral, topical, IV, etc.). See Specification at 18, paragraph [0096].
The therapeutic endpoints : “A method of preventing, treating, or alleviating a symptom” – plain an ordinary meaning. “Preventing”, “treating” and “alleviating” as discussed in the specification paragraphs [0079]-[0081] and do not require imported definitions, because the specification sets forth preferences for these claim terms. Further, with respect to the “treating” arm, the Specification uses the terms “symptoms” and “complications” interchangeably. Accordingly, the examiner interprets “treating … symptoms” as “treating … complications”. See Specification at 13-14, paragraph [0080].
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-5 and 13-14 Anticipated by WO’308
Claim(s) 1-5 and 13-14 is/are rejected under both 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by WO’308.4
WO’308 teaches administration of the active macitentan to a human wherein the administration is for the treatment and/or prevention of chronic thromboembolic pulmonary hypertension (CTEPH). See, e.g., WO’308 at 31, claim 1.
WO’308 at 2 expressly states that “Chronic thromboembolic pulmonary hypertension (CTEPH) is a complication of pulmonary embolism and a major cause of chronic PH leading to right heart failure and death [Kim et al., Chronic thromboembolic pulmonary hypertension. Eur. Respir. J. (2018), in press (https://doi.org/10.1183/13993003.01915-2018)].”.
It follows that the prevention of chronic thromboembolic pulmonary hypertension encompasses the prevention of pulmonary embolism because WO’308 states that CTEPH is a complication of pulmonary embolism. Alternatively, the treatment of chronic thromboembolic pulmonary hypertension encompasses the treatment of pulmonary embolism because WO’308 states that CTEPH is a complication of pulmonary embolism.
Accordingly, WO’308 teaches the prevention and/or treatment of pulmonary embolism comprising administering the active macitentan.
It follows that preventing pulmonary embolism prevents a symptom of a venous thromboembolic event, wherein the venous thromboembolic event is pulmonary embolism (claims 1-5), because no symptoms can present if the pulmonary embolism is prevented. Alternatively, the treatment of pulmonary embolism treats a symptom of a venous thromboembolic event, wherein the venous thromboembolic event is pulmonary embolism (claims 1-5), because the pulmonary embolism is treated.
Further, WO’308 teaches the same method comprising administering “a derivative or analog” of macitentan, wherein the “a derivative or analog” of macitentan is aprocitentan. See, e.g., WO’308 at 34-35, claims 30-35.
Therefore, claims 1-5 are anticipated by WO’308.
Regarding claims 13-14, WO’308 expressly teaches administration of a thromboprophylaxis regimen, wherein the thromboprophylaxis regimen comprises a antithrombotic agent. The thromboprophylaxis regimen is “chronic anticoagulation therapy”, and the antithrombotic agent is riociguat. See WO’308 at 2:
In addition to chronic anticoagulation therapy, each patient with CTEPH should receive treatment assessment starting with evaluation for pulmonary endarterectomy, which is the guideline recommended treatment. For technically inoperable cases, PH-targeted medical therapy is recommended (currently riociguat based on the CHEST studies), and balloon pulmonary angioplasty should be considered at a centre experienced with this challenging but potentially effective and complementary intervention.
WO’308 at 2.
See also, WO’308 at 32-33, claims 15-18 (teaching the method comprising administering macitentan and riociguat).
Accordingly, claims 13-14 are anticipated by WO’308.
Claims 1-6 Anticipated by Bochenek 2020 as Evidenced by Supporting Information and Diaz 2019
Claim(s) 1-6 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bochenek 2020 as Evidenced by Supporting Information5 and Diaz 2019.6
Bochenek 2020 teaches administration of the active bosentan (5 mg/kg BW weekly IP injection),7 which the examiner interprets as “a derivative or analog” of macitentan, to mice that had a venous thromboembolic event,8 wherein the administration “significantly reduced venous thrombus size at day 21.”9 Indeed, Bochenek 2020 teaches the subject matter of claims 1-6, and teaches the same experiment and results that Applicant found (DVT induced in mice by IVC ligature/stenosis model, followed by treatment with a small molecule endothelin receptor antagonist, wherein the treatment reduced thrombus size).
In particular, the subjects administered bosentan were specific End.TGFβRII-KO mice. Such mice are subjects directly within the scope of the instant claims. See Specification at 18, paragraph [0095] (explicitly stating that “subject” includes “any organism to which aspects of the invention can be administered, e.g., for experimental … purposes”, and continuing to state that for “research applications”, “subjects[] includ[e] rodents (e.g., mice, rats…)”.). Further, the mice received a therapeutic benefit as a result of the treatment (reduced thrombus size). As a result, Bochenek 2020 as Evidenced by Supporting Information and Diaz 2019 reads on claims 1-6.
These specific mice were generated because “Using whole genome microarray analysis of human endothelial cells outgrown from CTEPH PEA specimens, we observed a significant upregulation of TGFβ and associated signaling molecules (M.L. Bochenek, unpublished data). The present study was undertaken to examine the hypothesis that overexpression of TGFβ1 and activated TGFβ1 signaling in endothelial cells is causally involved in venous thrombus nonresolution and the development of thrombofibrosis in CTEPH.” Bochenek 2020 at 164.
End.TGFβRII-KO mice exhibit an exaggerated fibrotic phenotype that displays thrombus non-resolution and mimics vessels in patients with CTEPH. See, e.g., Bochenek 2020 at 166, right column, and reference the annexed supporting information as needed wherein it states “Online Figure”: (“To examine the importance of TGFβ signaling in endothelial cells for thrombus (non)-resolution, we generated mice in which TGFβRII was specifically deleted in endothelial cells (End.TGFβRII-KO).… Total (ie, latent) TGFβ1 levels in plasma did not differ; however, endothelial-specific deletion of TGFβRII was associated with significantly increased plasma levels of activated TGFβ1… In this regard, mPECs from End.TGFβRII-KO mice were found to over express factors involved in TGFβ activation, such as MMP9 … or TSP1.… Activated TGFβ1 plasma levels further increased at day 21 after IVC ligation in End.TGFβRII-WT (25.8-fold) and to a greater extent in End.TGFβRII-KO mice (27.4-fold; P=0.0377).”).
See also, e.g., Bochenek 2020 at 169 (“Endothelial deletion of TGFβRII was associated with significantly slower thrombus resolution … resulting in increased venous thrombus size at day 21 …. Analysis of mouse lungs revealed significantly higher numbers of vessels occluded with fibrinogen-positive, unresolved thrombotic material in End.TGFβRII-KO mice that had formed a thrombus compared with End.TGFβRII-WT mice…. Venous thrombi in End.TGFβRII-KO mice contained significantly higher amounts of fibrotic material … and interstitial collagen … compared with End.TGFβRII-WT animals. The SMA (smooth muscle actin-α)-positive area was also significantly increased…. Furthermore, SMA immunosignals frequently colocalized with CD31-positive cells lining vascular channels, which were increased in thrombi of End.TGFβRII-KO…, a finding reminiscent of vessels in patients with CTEPH (Figure 4B).”).
The data of Bochenek 2020 teach an activated TGFβ1 -> increased ET-1 -> EndMT -> thrombus nonresolution axis, wherein pharmacological “[i]nhibition of ET-1 with bosentan, an ET-1 receptor antagonist, reversed the conversion of endothelial cells to myofibroblasts and improved venous thrombus resolution but also inhibited thrombotic pulmonary obstructions.” Bochenek 2020 at 163. See also, Bochenek 2020 at 174-175 (discussing impact of elevated ET-1), see, e.g., in particular, right column of 174-175:
Plasma ET-1 levels in End.TGFβRII-KO animals were significantly elevated compared with End.TGFβRII-WT mice at baseline … and further increased to a significantly greater extent 21 days after IVC ligation …. At this time point, a strong ET-1 immunosignal was observed in resolving murine thrombi, particularly in those of End.TGFβRII-KO mice (Figure 8D). … Antagonization of endothelin receptors using bosentan reduced the outgrowth … and mesenchymal marker expression (Online Figure XIVC) of endothelial sprouts from aortic rings of End.TGFβRII-KO mice. Importantly, administration of bosentan following IVC ligation significantly reduced venous thrombus size at day 21 in End.TGFβRII-KO mice … to values similar to those observed in End.TGFβRII-WT mice (…; Figure 8E and 8F). The number of occluded pulmonary arteries also significantly decreased compared with control-treated End.TGFβRII-KO mice (…; Figure 3A through 3C). Flow cytometry analysis of 21 day-old venous thrombi showed that bosentan increased the relative number of CD31- or Cdh5-positive cells within thrombi…, whereas the percentage of CD31- or Cdh5-positive cells simultanously expressing FSP1 or SMA was significantly decreased compared with control-treated End.TGFβRII-KO mice (…; Figure 8G and 8H), confirming our in vitro data and underlining the importance of endothelin-1 signaling during thrombus nonresolution and EndMT in vivo.
Bochenek 2020 at 174-175.
Regarding claim 6, wherein the thrombosis comprises deep vein thrombosis, Bochenek 2020 teaches that tissue samples were obtained from patients with chronic thromboembolic pulmonary hypertension (“CTEPH”). See Bochenek 2020 at 163, first main paragraph, and at 165, left column, under “Studies Involving Human Tissue”. Of the patients with confirmed CTEPH, 94.7% of the patients had history of DVTs. See Bochenek 2020 Supporting Information at 16. Accordingly, patients with CTEPH may be having, may be prone to having, or may have had “a venous thromboembolic event”, wherein the “venous thromboembolic event” is a “DVT”. This places patients with CTEPH within the scope of the instant claim 6.
Now see Bochenek 2020 at 179, last paragraph, wherein it teaches administering an agent to block ET-1 signalling to treat patients with CTEPH, and states that this treatment protocol was in current clinical practice for patients with inoperable CTEPH:
Here we demonstrate that endothelin receptor antagonization prevented the TGFβ1-induced expression of receptors and transcriptional regulators involved in EndMT, SMA, and collagen expression and also restored venous thrombus size and the presence of pulmonary vaso-occlusions in End.TGFβRII-KO mice to findings in End.TGFβRII-WT mice. Although a causal role of endothelin-1 in CTEPH has not been directly demonstrated, ET receptor antagonists are prescribed in patients with inoperable CTEPH or persistent/recurrent pulmonary after PEA and have been shown to improve hemodynamic parameters and survival.55,56 Our findings of increased ET-1 expression in chronic murine venous thrombi, human CTEPH endothelial cells or PEA specimens and reversal of overactivated endothelial TGFβ signaling following endothelin receptor antagonization provide a pathophysiological basis of this current clinical practice and also support the usefulness of blocking endothelin-1 signaling beyond its vasoactive effects.
Bochenek 2020 at 179 (emphases added).
Accordingly, Bochenek 2020 teaches administration of an agent to block ET-1 signalling to treat patients with CTEPH, wherein the agent is at least bosentan, which is a derivative or analog of macitentan, and that the method was in current clinical practice. Given the prevalence of DVTs in patients with CTEPH, the examiner interprets Bochenek 2020 as teaching the method of the instant claim 5, wherein the venous thrombosis comprises deep vein thrombosis. Accordingly, it teaches the subject matter of claim 6.
To the extent that Applicant may disagree with the examiner’s interpretation that Bochenek 2020 teaches the subject matter of claim 6 with respect to patients with CTEPH, it nevertheless teaches the subject matter of claim 6 with respect to the treated mice subjects. The mice were subjected to induced venous thrombosis. See Bochenek 2020 Supporting Information at 2 (“Venous thrombosis was induced in male mice (12-14 weeks-of-age) by subtotal ligation of the inferior Vena cava (IVC) using a 5-0 Prolene suture (Ethicon) placed as a spaceholder alongside the IVC, as described.5 Side and back branches were not ligated.”).
This method of inducing a VTE in a mouse is consistent with the methodology to induce DVT in mouse models of DVT, and is consistent with the method Applicant used to induce DVT in mice by stenosis. See Specification at 56, paragraph [00335]. See also, Diaz 2019 at 700-702 (discussing the stenosis model of DVT).
Accordingly, Bochenek 2020 as Evidenced by Supporting Information and Diaz 2019 teaches the subject matter of claim 6 with respect to mice.
Therefore, claims 1-6 are anticipated by Bochenek 2020 as Evidenced by Supporting Information and Diaz 2019.
Claims 1-6 and 13-15 Anticipated by Solis 2011
Claim(s) 1-6 and 13-15 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Solis 2011.10
Solis 2011 teaches administration of the active bosentan,11 which the examiner interprets as “a derivative or analog” of macitentan, to an 82-year-old woman that had a venous thromboembolic event (DVT),12 wherein the administration was “successful in the treatment of this case of refractory chronic venous ulcer.”13
Solis 2011 explains that chronic venous ulcers (CVUs) manifest from complications of DVTs, wherein the complications of DVTs are post-thrombotic syndrome (PTS), which leads to CVUs. See Solis 2011 at 169:
Post-thrombotic syndrome (PTS) is a long-term complication of deep venous thrombosis (DVT). About 20–50% of patients develop PTS within 1–2 years of having suffered a symptomatic DVT. Severe PTS, which may manifest itself as a venous ulceration, occurs in 5–10% of the cases of PTS.1,2 Both chronic venous insufficiency and the associated venous hypertension have been advocated as the main features in the pathogenesis of PTS. In addition to the prior thrombotic event, primary valvular incompetence is also an important pathogenic factor of chronic venous ulcer (CVU). Results of the treatment of CVU are usually disappointing, especially in elderly hypertensive women.
Solis 2011 at 169.
The claims expressly permits the “treating” arm to include treating complications, which it uses interchangeably with symptoms. See Specification at 13-14, paragraph [0080]:
The terms “treat,” “treatment,” and “treating” can refer to the management and care of a subject for the purpose of combating a condition, disease or disorder, such as a venous thromboembolic event or cancer-associated thrombosis, in any manner in which one or more of the symptoms of a disease or disorder are ameliorated or otherwise beneficially altered. The term can include the full spectrum of treatments for a given condition from which the patient is suffering, such as administration of the active compound for the purpose of: alleviating or relieving symptoms or complications; delaying the progression of the condition, disease or disorder; curing or eliminating the condition, disease or disorder; and/or preventing the condition, disease or disorder, wherein “preventing” or “prevention” can refer to the management and care of a patient for the purpose of hindering the development of the condition, disease or disorder, and includes the administration of the active agents to prevent or reduce the risk of the onset of symptoms or complications.
Specification at 13-14, paragraph [0080].
Accordingly, Solis 2011 teaches the treating arm with respect to the subject matter of claims 1-6, and claims 1-6 are anticipated by Solis 2011.
Regarding claims 13-15, the claims require the method of claim 1, “further comprising administering to the subject a thromboprophylaxis regimen”, wherein the thromboprophylaxis regimen comprises “an antithrombotic agent”, wherein the “antithrombotic agent” comprises “warfarin, heparin, dabigatran, rivaroxaban, or apixaban.” The claims do not require a certain time period wherein the thromboprophylaxis regimen is administered.
Solis 2011 expressly teaches the method further comprising administering to the subject a thromboprophylaxis regimen, wherein the thromboprophylaxis regimen comprises “an antithrombotic agent”, wherein the “antithrombotic agent” comprises heparin. See Solis 2011 at 170, left column (“One year after the DVT episode, she developed a post-thrombotic CVU, which was treated following the standard treatment (general postural measures, elastic dressing, pentoxifiline, low weight heparine, systemic phlebotropics and antibiotherapy).”) (emphasis added).
Accordingly, the method taught by Solis 2011 further comprises administering to the subject a thromboprophylaxis regimen of low weight heparine.
Therefore, claims 13-15 are anticipated by Solis 2011.
Claims 1-5, 7-9 and 10-12 Anticipated by Higo 2014 as Evidenced by Lu 2021
Claim(s) 1-5, 7-9 and 10-12 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Higo 201414 as Evidenced by Lu 2021.15
Higo 2014 teaches administration of the active bosentan,16 which the examiner interprets as “a derivative or analog” of macitentan, to a 61-year-old man that had colorectal cancer and an additional venous thromboembolic event (Pulmonary tumor thrombotic microangiopathy (“PTTM”)),17 as a combination therapy with an anti-cancer therapeutic regimen comprising chemotherapy,18 with prior treatment comprising chemotherapy and surgery.19 The treatment was successful, but regrettably the patient died a year after discharge due to a respiratory infection.20 While the physicians were unable to point to which exact agent in the combination therapy was the most effective,21 the method that Higo 2014 as evidenced by Lu 2021 teaches reads on at least claims 1-5, 7-9 and 10-12. The examiner will address PTTM and “a venous thromboembolic event”, and that the administered chemotherapy agent is associated with increased incidence of a venous thromboembolic event, when Lu 2021 is discussed.
Regarding claim 8, the patient was afflicted with a solid tumor cancer (colorectal cancer and tubular adenocarcinoma), which was treated with rounds of chemotherapy (bevacizumab) and surgery; the colorectal cancer eventually went into remission, but unfortunately the cancer spread at least to the lungs.22 Colorectal cancer is a solid tumor cancer, see Specification at 15, paragraph [0084]. The cancer spread to the lungs. The physicians do not report lymphoma, myeloma, leukemia, or neoplasia without solid formation. Accordingly, the examiner interprets the cancer found in the patient’s lungs as a solid tumor cancer wherein the solid tumor cancer comprises lung cancer, claim 9.
Regarding claims 10-12, as discussed, the patient was initially treated with bevacizumab. See Higo 2014 at 2595 (“After surgery, chemotherapy with bevacizumab was administered.”). Bevacizumab is therefore a chemotherapy agent. Further, it is associated with an increased incidence of a venous thromboembolic event. See Lu 2021 at 775 (note, that DIC used in this passage is an abbreviation for disseminated intravascular coagulation):
It is generally considered that DIC and thrombi are contraindications to angiogenesis inhibitors. Thromboembolic events and thrombocytopenia are common side effects of bevacizumab. Serum VEGF of tumor patients is mainly derived from platelets, and 97% of bevacizumab binds to serum VEGF (27,28). It has been demonstrated that platelets can absorb bevacizumab and release it at the site of the endothelial injury to participate blood coagulation and intimal proliferation. These results indicate that the target of bevacizumab is closely related to coagulation and thrombosis, although the complex interactions between them require further investigation.
Lu 2021 at 775 (emphases added).
Regarding PTTM, the main clinical manifestations include disseminated intravascular coagulation (see, e.g., Lu 2021 at 367, Abstract) and elevated D-dimer (see Lu 2021 at 768, few lines down). Elevated D-dimer is specific inclusion criteria for the patients Applicant seeks to treat. See Specification at 61, paragraph [00371]. See also, Lu 2021 at 774 (“PTTM is caused by small tumor emboli in veins and embolus-induced endovascular fibrosis.”). Small tumor emboli in veins is within the scope of “a venous thromboembolic event” of the current claims.
The pathophysiological changes of PTTM cause thromboembolism, hypercoagulable blood, and result from tumor cells entering the blood stream that in turn activate the coagulation system. See Lu 2021 at 773:
The pathogenesis of PTTM is still unclear. Currently, the accepted pathogenesis is that malignant tumor cells form tiny tumor emboli in pulmonary blood vessels, which destroy vascular endothelium, form a pre-coagulation environment, and then activate the coagulation system and diffusely embolize the microvessels. This in turn leads to thrombocytopenia and intimal fibrocyte hyperplasia in small pulmonary blood vessels, lumen stenosis, pulmonary vascular structure remodeling, and ultimately to pulmonary hypertension (1). Tumor cells express a large number of tissue factors (TF) and VEGF, which play an important role in tumor metastasis, angiogenesis, growth, and thrombosis, and can induce vascular endothelial damage and further activate the coagulation system (18). The injured vascular endothelium secretes PDGF, osteopontin (OPN), and a variety of vasoactive factors. OPN can promote the adhesion, migration, and proliferation of fibroblasts, vascular endothelial cells, and smooth muscle cells. Cluster of differentiation 44 (CD44) is a cell adhesion molecule that can induce inflammation, autoimmune diseases, angiogenesis, and atherosclerosis. Tumor thrombus immunohistochemistry has shown that the positive rate of VEGF and TF were 96.6% and 100%, respectively (8). Therefore, the detection of the expression of various molecules in tumor cells of PTTM patients may provide a basis for targeted biological therapy (5).
Lu 2021 at 773 (emphases added); see also Lu 2021 at 775:
The clinical pathophysiological changes of PTTM are mainly due to: (I) malignant carcinoma progression, tumor cell dissemination to the pulmonary blood and lymphatic vessels, and infiltration into the surrounding lumen (1,15); (II) the binding of the highly expressed VEGF molecule on the cell surface to the VEGF on vascular endothelial cells stimulates intima proliferation and thickening, resulting in intimal proliferation and lumen stenosis (1,26); (III) tumor cell emboli activation of the coagulation system, leading to thromboembolism of micro vessels, which is not only limited to the lungs, but also occurs in the micro-vessels of other organs, ultimately leading to multiple organ functional damage and even failure (1,3).
Lu 2021 at 755 (emphases added).
In the event that Applicant argues that no pulmonary thromboembolism was found for the patient of Hugo 2014,23, this finding was consistent as Lu 2021 at 733 explains that PTTM patients typically will not exhibit pulmonary embolism on CT scans (“Typically, patients with progressive dyspnea accompanied by hypercoagulable blood will not exhibit signs of pulmonary embolism on CT pulmonary angiography.”).24
Accordingly, the method that Higo 2014 as Evidenced by Lu 2021 teaches reads on at least claims 1-5, 7-9 and 10-12. It does so in at least two ways. First, if the intended use recitation in the preamble “A method of preventing, treating, or alleviating a symptom of a venous thromboembolic event in a subject” is afforded little patentable weight, the actives and therapeutic endpoints, patient populations, and routes of administration are all taught expressly by Higo 2014. Second, a venous thromboembolic event in a subject may be interpreted as either the colorectal cancer and tubular adenocarcinoma causing a venous thromboembolic event, or PTTM causing a venous thromboembolic event, or the administration of the chemotherapy agent bevacizumab causing a venous thromboembolic event. Further, in each case, the venous thromboembolic event is at least associated with cancer (claim 5), and administration of the actives is all that is required in the context of a patient having, or be prone to having, or a patient that had a venous thromboembolic event. The patient of Higo 2014 satisfies these criteria having been diagnosed with colorectal cancer, tubular adenocarcinoma, and PTTM, and was administered bevacizumab prior to treatment with bosentan, and subsequently administered bevacizumab with bosentan.
Therefore, claims 1-5, 7-9 and 10-12 are anticipated by Higo 2014 as Evidenced by Lu 2021.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-6 Obvious over Bochenek 2020 as Evidenced by Supporting Information and Diaz 2019, in view of WO’308
Claim(s) 1-6 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bochenek 2020 as Evidenced by Supporting Information and Diaz 2019,25 in view of WO’308.26
The findings of fact, rejections, and entire discussions of the references as cited in the sections regarding anticipation are fully incorporated herein.
As discussed, Bochenek 2020 as Evidenced by Supporting Information and Diaz 2019 teaches the subject matter of claims 1-6, and teaches the same experiment and results that Applicant found (DVT induced in mice by IVC ligature/stenosis model, followed by treatment with a small molecule endothelin receptor antagonist, wherein the treatment reduced thrombus size).
Further, as discussed, Bochenek 2020 as Evidenced by Supporting Information and Diaz 2019 teaches administering an agent to block ET-1 signalling to treat patients with CTEPH, and states that this treatment protocol was in current clinical practice for patients with inoperable CTEPH.
Further, as discussed, Bochenek 2020 as Evidenced by Supporting Information and Diaz 2019 expressly teaches a method of administering an endothelin receptor inhibitor (bosentan) to treat an induced DVT in a mouse model of DVT (claim 6).
Further, as discussed, Bochenek 2020 as Evidenced by Supporting Information and Diaz 2019 at 179 expressly teaches that its method applies generally to ET-1 expression and blocking endothelin-1 signaling (“Our findings of increased ET-1 expression in chronic murine venous thrombi, human CTEPH endothelial cells or PEA specimens and reversal of overactivated endothelial TGFβ signaling following endothelin receptor antagonization provide a pathophysiological basis of this current clinical practice and also support the usefulness of blocking endothelin-1 signaling beyond its vasoactive effects.”).
However, Bochenek 2020 as Evidenced by Supporting Information and Diaz 2019 does not expressly teach administering the endothelin receptor inhibitor (macitentan) to treat an induced DVT in a mouse model of DVT.
One of ordinary skill in the art at the time of filing would have a reasonable expectation of success in treating an induced DVT in a mouse model of DVT because WO’308 teaches that the endothelin receptor inhibitor (macitentan) exhibits “maximal or near-maximal effect of macitentan in rats is 10 mg/kg.” WO’308 at 3. Further, WO’308 teaches that at the maximal dose, macitentan blocks binding of ET-1 to endothelin receptors. See WO’308 at 4 (“In a multiple-ascending dose study evaluating 1 mg, 3 mg, 10 mg, and 30 mg dosages of macitentan in healthy human subjects, plasma ET-1 concentrations at steady-state showed a dose-dependent increase, with no further increase beyond the 10 mg oral dose, indicating blockade at this dosage. (Id. at 40).”).
Rats are murine animals, just as mice are. Bochenek 2020 expressly states at 179 that blocking ET-1 by administering any endothelin receptor inhibitor will cause the same effect. One of ordinary skill in the art at the time of filing would reasonably expect that administration of the endothelin receptor inhibitor macitentan to mice, instead of rats, would result in the blockade of ET-1 binding within the mice, because rats and mice are both murine animals. Therefore, following Bochenek 2020, one of ordinary skill in the art at the time of filing would reasonably expect that administering macitentan to an End.TGFβRII-KO mouse with an induced DVT would result in reduced venous thrombus size. Therefore, one of ordinary skill in the art at the time of filing would have a reasonable expectation of success in treating a DVT comprising administering macitentan to an End.TGFβRII-KO mouse with an induced DVT.
Accordingly, claims 1-6 were obvious at the time of filing.
Claims 1-15 Obvious over Bochenek 2020 as Evidenced by Supporting Information and Diaz 2019, in view of WO’308, Higo 2014 as Evidenced by Lu 2021, and Khadka 2015 as Evidenced by Zhang 2017
Claim(s) 1-15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bochenek 2020 as Evidenced by Supporting Information and Diaz 2019,27 in view of WO’308,28 Higo 2014 as Evidenced by Lu 2021,29 and Khadka 201530 as Evidenced by Zhang 2017.31
The findings of fact, rejections, and entire discussions of the references as cited in the sections regarding anticipation are fully incorporated herein.
Further, the findings of fact, rejections, and entire discussions of the references cited in the preceding section regarding the obviousness of claims 1-6 are fully incorporated herein.
Bochenek 2020 as Evidenced by Supporting Information and Diaz 2019, in view of WO’308, do not appear to expressly teach the administration of an endothelin receptor inhibitor in the context of treating cancer.
However, as discussed, Higo 2014 as Evidenced by Lu 2021 expressly teaches the administration of an endothelin receptor inhibitor in the context of treating cancer.
One of ordinary skill in the art at the time of filing would have a reasonable expectation of success in preventing, treating, or alleviating a symptom of a venous thromboembolic event in a subject afflicted with cancer, wherein the solid tumor cancer comprises at least lung cancer, by administering an endothelin receptor inhibitor because Higo 2014 as Evidenced by Lu 2021 teaches that the combination of an endothelin receptor inhibitor (bosentan), with a chemotherapy regimen, resulted in the successful treatment of the patient’s PTTM caused by colorectal cancer that spread to the lungs. Moreover, Khadka 2015 as Evidenced by Zhang 2017 teaches an ET-1 axis for lung cancers, and that administration of an endothelin receptor antagonist (macitentan exemplified in Khadka 2015) with chemotherapy synergistically improves patient prognoses. Therefore, the ET-1 axis was known to be therapeutically linked between the treatment of lung cancers and the resolution of a venous thromboembolic event (e.g., Bochenek 2020 and WO’308).
Indeed, the physicians of Higo 2014 state that “Although the administration of 5 L of oxygen was required, the patient was discharged after three months of hospitalized treatment. He did not experience worsening of his pulmonary hypertension. However, he died from respiratory failure due to an influenza infection 12 months later.” Higo 2014 at 2597. Lu 2021, which cites Higo 2014 in its review of the clinical literature regarding PTTM, remarks at page 774 that PTTM patients have just days to live after oxygen support is required (“The median survival time, from the time that the patient requires oxygen support, is 9 days (5).”).
No additional incidents of a venous thromboembolic event caused by the administration of bevacizumab in combination with bosentan were reported by the physicians in Higo 2014.
As discussed, the chemotherapy agent bevacizumab was known to induce thromboembolic events and thrombocytopenia. See Lu 2021 at 775.
Further, as discussed, PTTM is a devasting disease “with an appalling prognosis”. See Lu 2021 at Abstract. Clinical manifestations include disseminated intravascular coagulation (see, e.g., Lu 2021 at 367, Abstract) and elevated D-dimer (see Lu 2021 at 768, few lines down).
The pathophysiological changes of PTTM cause thromboembolism, hypercoagulable blood, and result from tumor cells entering the blood stream that in turn activate the coagulation system. See, e.g. Lu 2021 at 773 and at 775 (sections cited in 102 section). See also, Lu 2021 at 774 (“PTTM is caused by small tumor emboli in veins and embolus-induced endovascular fibrosis.”). The patients exhibit systemic clotting and bleeding due to the disseminated intravascular coagulation. See Lu 2021 at 775 (“tumor cell emboli activation of the coagulation system, leading to thromboembolism of micro vessels, which is not only limited to the lungs, but also occurs in the micro-vessels of other organs, ultimately leading to multiple organ functional damage and even failure (1,3).”).
That the patient of Higo 2014 did not succumb to worsening of the symptoms of PTTM appeared to surprise the physicians. As discussed, the physicians state “The most effective agent in this combination therapy is unclear.” Higo 2014 at 2598. Further, they state “Comprehensive studies are needed to elucidate the mechanism by which molecular-target drugs exert their effects during PTTM.” Id.
Further, Lu 2021, in citing Higo 2014, states that “a combination treatment involving chemotherapy coupled with the anti-VEGF receptor antibody, bevacizumab (8,15), anticoagulant therapy, and drugs for lowering pulmonary hypertension [such as endothelin antagonists (sildenafil), cyclic prostaglandin analogs, and phosphodiesterase-5 inhibitors (bosentan)] is effective in some cases of PTTM.” Lu 2021 at 774. Despite Lu 2021 making a typographical error (swapping sildenafil and bosentan roles), Lu 2021 expressly confirms that including endothelin antagonists is effective in some cases of PTTM.
While Higo 2014 as Evidenced by Lu 2021 do not expressly teach an ET-1 axis for lung cancers, Khadka 2015 as Evidenced by Zhang 2017 does.
See, e.g., Khadka 2015 at 55:
Many tumors have been found to express ETs and ETRs. ET pathways have been shown to play important roles in tumor cell proliferation, migration and invasion and vascular differentiation. The ET axis has been reported to be of relevance in lung cancer, colon cancer, renal cancer, cervical cancer, brain tumors and ovarian cancer. Macitentan alone decreased the expression of survival pathways but was ineffective or was only marginally effective alone as an antitumor agent therefore leading to strong synergism with chemotherapy.[15,16]
Khadka 2015 at 55 (emphases added).
See, e.g., Zhang 2017 at Abstract (“In the present study, Endostar, a recombinant human endostatin injectable drug, was also used, and it was assessed whether the sensitivity of tumor cells to this drug could be increased by silencing ET-1. Both in vivo and in vivo tests were carried out in the present study. The experimental data indicated that ET-1 silencing can inhibit tumor cell proliferation and invasion, particularly in the presence of Endostar.”).
See also, Zhang 2017 at 4391-4392 (“In the present study, ET-1 was silenced via RNA interference (RNAi), and the proliferation of A549 cells and the expression of apoptosis, growth and invasion-associated factors, including RhoA/C, vascular endothelial growth factor (VEGF), pigment epithelium-derived factor (PEDF), AKT, E-cadherin and cyclooxygenase (Cox)-2, were then examined. It was observed that ET-1 RNAi can inhibit A549 cells proliferation and invasion more effectively than Endostar, which suggested that ET-1 RNAi may be a new effective strategy to treat lung cancer.”) (emphasis added).
The combination of the references directly results in the subject matter of claims 1-12.
Regarding claims 13-15, wherein the method further comprises administering to the subject a thromboprophylaxis regimen, wherein the thromboprophylaxis regimen comprises an antithrombotic agent, wherein the antithrombotic agent comprises named specific APIs, Higo 2014 expressly avoided including standard anticoagulation therapy because the physicians understood it to be contraindicated in combination with the chemotherapy agent administered. See Higo 2014 at 2596 (“We did not conduct anticoagulation therapy because one possible side effect of bevacizumab treatment includes bleeding. No other side effects were apparent.”). Lu 2021 acknowledges that adding such treatments is controversial. See Lu 2021 at 774 (“However, anticoagulation therapy and lowering pulmonary hypertension remain controversial…”). Lu 2021 continues to discuss Higo 2014, and lists the medications the patient received. It is unclear if any of these medications comprise “a thromboprophylaxis regimen” or “an antithrombotic agent” because Applicant never explains precisely what these claim terms mean.
However, Lu 2021 continues, in discussing the severity of PTTM, to state that despite the controversial nature of including anticoagulation therapy with an agent that lowers pulmonary hypertension (e.g., an endothelin receptor antagonist), the alternative is near certain death. See Lu 2021 at 775 (“Therapeutically, considering the critical nature of PTTM and the accompanying serious complications (i.e., myocardial damage and severe thrombocytopenia), as well as the potentially severe adverse reactions of anti-tumor drugs, it is extremely difficult to treat PTTM clinically, despite the potential alleviating effects of treatment.”).
Lu 2021 teaches that although controversial, the anticancer regimen may further comprise administering heparin. See Lu 2021 at 776 (“Furthermore, although the combination of anticoagulation and VEGF inhibitors will increase the risk of bleeding, the administration of low molecular weight heparin and fresh-frozen plasma in a reasonable dose and order to establish a balance between bleeding and coagulation is conducive to the correction of DIC.”).
Accordingly, one of ordinary skill in the art at the time of filing would have a reasonable expectation of success in preventing, treating, or alleviating a symptom of a venous thromboembolic event in a subject afflicted with cancer, wherein the solid tumor cancer comprises at least lung cancer, by administering an endothelin receptor inhibitor, wherein the subject is also treated with chemotherapy, and is also treated with the antithrombotic agent heparin. Under Higo 2014, bosentan was exemplified as the endothelin receptor inhibitor administered. Bosentan is analogous to macitentan being a drug of the same class (administration results in blocking ET-1 binding) with structural similarity. Khadka 2015 teaches Macitentan in the context of cancers. Therefore, one of ordinary skill in the art at the time of filing would reasonably expect that bosentan could be exchanged for macitentan in the method taught by Higo 2014. Lu 2021 teaches that adding heparin was reasonable given the severity of PTTM, setting aside the concerns raised by the physicians in Higo 2014 when the alternative is near certain death.
Therefore, claims 1-15 were obvious at the time of filing.
Prior Art Cited but not Applied
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Asteggiano, Riccardo. "Physiopathology and Toxic Heart Effects of Chemotherapy Drugs." Cardiac Management of Oncology Patients: Clinical Handbook for Cardio-Oncology. Cham: Springer International Publishing, 2015. 23-97, hereinafter “Asteggiano”.
Teaches (throughout) that many chemotherapy agents induce endothelial damage and cause thrombus formation. See, e.g., Asteggiano at 27 (“Pro-coagulation condition is common in subjects with malignancies. Many chemotherapy agents may enhance this state leading to venous and arterial thromboembolism and clinical occurrence of pulmonary embolism or peripheral venous or arterial thrombosis.”), and at 27, Fig. 2.1:
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Asteggiano at 27.
Further teaches that endothelin receptor antagonists were in clinical practice to treat cancer patients, particularly to protect against cardiotoxicity. See, e.g., Asteggiano at 46:
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Asteggiano at 46.
Kearon, Clive, et al. "Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report." Chest 149.2 (2016): 315-352, hereinafter “Kearon 2016”. Kearon 2016 is citation 21 of Winter 2017, which was cited in the claim interpretation section.
Kearon 2016 teaches the subject matter of claims 13-15 (i.e., standard thromboprophylaxis regimens. See, e.g., Kearon 2016 at 315 (“For VTE and no cancer, as long-term anticoagulant therapy, we suggest dabigatran (Grade 2B), rivaroxaban (Grade 2B), apixaban (Grade 2B), or edoxaban (Grade 2B) over vitamin K antagonist (VKA) therapy, and suggest VKA therapy over low-molecular-weight heparin (LMWH; Grade 2C). For VTE and cancer, we suggest LMWH over VKA (Grade 2B), dabigatran (Grade 2C), rivaroxaban (Grade 2C), apixaban (Grade 2C), or edoxaban (Grade 2C). We have not changed recommendations for who should stop anticoagulation at 3 months or receive extended therapy.”). Additional considerations of medications and interventions based on certain disease states are taught throughout.
Asteggiano in view of Kearon 2016 likely results in the subject matter of most or all of the claims.
Conclusion
No claims allowed.
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/C.E.R./Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
1 Hyndman, Kelly A., Michael M. Miyamoto, and David H. Evans. "Phylogeny, taxonomy, and evolution of the endothelin receptor gene family." Molecular phylogenetics and evolution, vol. 52, no. 3 (2009): 677-687, hereinafter “Hyndman 2009”.
2 Teerapuncharoen, Krittika, and Remzi Bag. "Chronic thromboembolic pulmonary hypertension." Lung, vol. 200, no. 3 (29 May 2022): 283-299, hereinafter “Teerapuncharoen 2022”.
3 Winter, M‐P., G. H. Schernthaner, and Irene M. Lang. "Chronic complications of venous thromboembolism." Journal of thrombosis and haemostasis, vol. 15, no. 8 (2017): 1531-1540, hereinafter “Winter 2017”.
4 CSONKA, DÉNES, et al., “PHARMACEUTICAL COMPOSITION COMPRISING MACITENTAN FOR THE TREATMENT OF CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION”, International Publication No. WO 2020152308 A1, published 2020-07-30, hereinafter “WO’308”.
5 Bochenek, Magdalena L., et al. "Activated endothelial TGFβ1 signaling promotes venous thrombus nonresolution in mice via endothelin-1: potential role for chronic thromboembolic pulmonary hypertension." Circulation Research vol. 126, no. 2, pp. 162-181 (2020), hereinafter “Bochenek 2020”. The supporting information/supplemental material is available online at the journal’s website, and the one used is annexed hereto (there are four individual pieces of supporting information on the website, and two of them appear to be identical (the 54 page documents). Only the first 54 page document was considered. The supporting information is also referred to herein as “Bochenek 2020 Supporting Information”. Further, the Supporting Information is essential to prove that the Bochenek 2020 contains an enabled disclosure, because it provides “[a] detailed description of all materials and methods” described in the article. Bochenek 2020 at 164, right column under the “METHODS” heading. Also gives figures referenced in text.
6 Diaz, Jose A., et al. “Choosing a mouse model of venous thrombosis: a consensus assessment of utility and application”, Journal of Thrombosis and Haemostasis, vol. 17, no. 4, pp. 699-707 (2019), hereinafter “Diaz 2019” (also cited in one of the IDSs received on 09/24/2024 as NPL cite 23). Diaz 2019 is cited to explain the meaning of a term used in the primary reference (the term being the particular model of DVT used in the study of Bochenek 2020), and to show a characteristic not disclosed in the reference is inherent (that the particular model of DVT used in the study induces DVT in mice).
7 See Bochenek 2020 Supporting Information at 2 (“In some animals, bosentan (Tocris; 5 mg/kg BW) was administered via intraperitoneal injection, beginning at day 1 after surgery and once per week thereafter until sacrifice at day 21, as published before.6,7 Mice injected with vehicle alone were used as control.”).
8 See Bochenek 2020 at 164 (“Venous thrombosis was induced in mice by subtotal ligation of the inferior vena cava (IVC) over a spaceholder (5-0 Prolene suture; Ethicon).”). See also, Bochenek 2020 Supporting Information at 2 (“Venous thrombosis was induced in male mice (12-14 weeks-of-age) by subtotal ligation of the inferior Vena cava (IVC) using a 5-0 Prolene suture (Ethicon) placed as a spaceholder alongside the IVC, as described.5 Side and back branches were not ligated.”).
9 Bochenek 2020 at 174, right column, last few lines. See also, Bochenek 2020 at 176 (“Importantly, findings of enhanced endothelial sprouting, mesenchymal lineage transition, and venous thrombus nonresolution could be reversed by endothelin receptor antagonization.”) (emphasis added); see also, Bochenek 2020 at 179 (“Here we demonstrate that endothelin receptor antagonization prevented the TGFβ1-induced expression of receptors and transcriptional regulators involved in EndMT, SMA, and collagen expression and also restored venous thrombus size and the presence of pulmonary vaso-occlusions in End.TGFβRII-KO mice to findings in End.TGFβRII-WT mice.”); see also, Bochenek 2020 at 163, top right bullet point (“Inhibition of ET-1 with bosentan, an ET-1 receptor antagonist, reversed the conversion of endothelial cells to myofibroblasts and improved venous thrombus resolution but also inhibited thrombotic pulmonary obstructions.”).
10 Solís, J. V., J. L. Portero, and L. Ribé. "Venous giant post-thrombotic chronic ulcer: successful treatment with Bosentan." Phlebology 26.4 (2011): 169-172, hereinafter “Solis 2011”.
11 See Solis 2011 at 170 (“The initial dose we prescribed was 62.5 mg bis in die (b.i.d.) during the first four weeks, and 125 mg b.i.d. afterwards.”).
12 See Solis 2011 at Abstract (“We present the case of an 82-year-old woman with a previous medical history of severe hypertension and a deep vein thrombosis three years before. A refractory giant chronic venous ulcer in her left leg was treated with Bosentan.”); see also, Solis 2011 at 170 (“Recanalization after the DVT episode was not observed in the phlebographic ultrasound–Doppler study, which showed a complete obstruction of the left leg femoropopliteal axis. One year after the DVT episode, she developed a post-thrombotic CVU, which was treated following the standard treatment (general postural measures, elastic dressing, pentoxifiline, low weight heparine, systemic phlebotropics and antibiotherapy). After two years, the ulcer was giant, measuring 13.5 × 8 × 1.5 cm (Figure 1), and extremely painful, requiring opioid treatment. The patient could neither walk normally nor carry out her daily chores. An off-label treatment with Bosentan was proposed to the patient and accepted after comprehensive explanations.”) (emphases added).
13 See Solis 2011 at Abstract; see also Solis 2011 at 170 (“ After one week, pain in the left leg completely disappeared and the patient could not only stop opioid treatment, but also start walking again. Her general condition improved in a similar way. Complete evolution of the CVU and its chronology are shown in Figures 2–6. The patient experienced only minor manageable side effects (gastric discomfort and dizziness) in the first few days after the beginning of the treatment, which completely disappeared after a week. She also presented a mild and transient increase of the liver function tests, which spontaneously resolved without needing to withdraw Bosentan treatment. A worsening of the ulcer appearance was observed after a transient stop of the treatment due to administrative problems of the Bosentan supply. When Bosentan treatment was resumed six weeks later, a significant improvement of the CVU was achieved, especially reducing the depth of the ulcer and improving the appearance of the ulcer verge (Figure 4). After three months of Bosentan treatment, the resolution of the ulcer was almost complete (Figure 6). General postural measures and elastic dressing were continued throughout the Bosentan treatment. In addition, we periodically collected ulcer cultures and antibiotherapy was administered when necessary, under conditions of routine clinical practice.”).
14 Higo, Kenjuro, et al. "Successful antemortem diagnosis and treatment of pulmonary tumor thrombotic microangiopathy." Internal Medicine, vol. 53, no. 22 (2014): 2595-2599, hereinafter “Higo 2014”.
15 Lu, Lan, et al. "Bevacizumab combined with pemetrexed successfully treated lung adenocarcinoma complicated with pulmonary tumor thrombotic microangiopathy: a case report and literature review." Annals of Palliative Medicine, vol. 10, no. 1 (2021): 76777-76777, hereinafter “Lu 2021”. Lu 2021 is cited to explain the meaning of a term used in the primary reference and/or to show that a characteristic not disclosed in the reference is inherent. The term/condition PTTM has displays a certain inherent pathogenesis, which is reviewed in Lu 2021. Further, Lu 2021 teaches that administration of the chemotherapy agent bevacizumab is associated with increased incidence of thromboembolic events.
16 See, e.g., Higo 2014 at 2598, Figure 4; see also, Higo 2014 at 2596 (“The patient was then diagnosed with PTTM. Bosentan and tadalafil were prescribed to decrease the pulmonary hypertension, and furosemide and spironolactone were administered in order to treat his heart failure.”).
17 See Higo 2014 at 2595, Introduction (“Pulmonary tumor thrombotic microangiopathy (PTTM) is characterized by fibrocellular intimal proliferation of the small pulmonary arteries and arterioles in carcinoma patients (1).”); see also, Higo 2014 at 2597 (“The mechanisms of action of PTTM are thought to occur through tumor cell occlusion of the small arteries and arterioles, the activation of coagulation systems, and the release of inflammatory mediators and growth factors (3).”); see also infra discussion of Lu 2021.
18 Treatment began with bevacizumab but was discontinued due to adverse events. See Higo 2014 at 2595, right column. However, it was restarted after PTTM was diagnosed. See Higo 2014 at 2596, last paragraph of left column to right column (stating that bosentan, tadalafil, furosemide, spironolactone, imatinib, bevacizumab and S-1 were administered).
19 See Higo 2014 at 2595-2596 (discussing the patient’s history), see, e.g., Higo 2014 at 2595 (“A 61-year-old man was diagnosed with colorectal cancer and had an abdominal operation in 2009. A pathological examination revealed tubular adenocarcinoma. The patient remained in good health for 16 months. However, recurrence of his colorectal cancer was detected in April 2011, and he underwent another operation. After surgery, chemotherapy with bevacizumab was administered.”)
20 See Higo 2014 at 2597, top left paragraph.
21 See Higo 2014 at 2598 (“As observed in our case, the prognosis of PTTM may be improved by combination therapy. The most effective agent in this combination therapy is unclear.”).
22See e.g., Higo 2014 at 2596 (“Positron emission tomography and computed tomography (PET-CT) showed that there was no recurrence of the rectal cancer, but small lung metastases were found.”); see also, Higo 2014 at 2597, Figure 3 (indicating tumors in the pulmonary arterial blood).
23 See Hugo 2014 at 2596 (“A mosaic pattern was observed by chest CT, but pulmonary thromboembolism was not detected.”).
24 See also, Lu 2021 at Abstract (“Chest computed tomography (CT) shows no distinctive findings, and PTTM is often unrecognized and universally underdiagnosed, with an appalling prognosis.”).
25 Cited in the section regarding anticipation (same collection of references).
26 Cited in the section regarding anticipation.
27 Cited in the section regarding anticipation (same collection of references).
28 Cited in the section regarding anticipation.
29 Cited in the section regarding anticipation (same collection of references).
30 Khadka, Anjan, et al. "Macitentan: An important addition to the treatment of pulmonary arterial hypertension." Journal of Pharmacology and Pharmacotherapeutics, vol. 6, no. 1 (2015): 53-57, hereinafter “Khadka 2015”.
31 Zhang, Zhen-Yu, et al. "Effects of silencing endothelin-1 on invasion and vascular formation in lung cancer." Oncology Letters, vol. 13, no. 6 (2017): 4390-4396, hereinafter “Zhang 2017”.
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