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 .
Claims Status
Claims 1-16 are pending. Claims 7-12 and 15-16 are withdrawn. Claims 1-6 and 13-14 are presently considered.
Election/Restriction
Applicant’s election without traverse of Group I1 (methods of treating cancer, claims 1-7 and 13-15 as filed 1/28/2026) and the patentably indistinct subgenus of methods comprising the administration of a Connexin432 in combination with dabrafenib to subjects, to treat cancer, wherein the Connexin43 is administered via any administration route at an unspecified “therapeutically effective amount”, in the reply filed on 1/28/2026 is acknowledged.
The originally elected species is identified as reading upon instant claims 1-6 and 13-14.
Following extensive search and examination, the originally elected subgenus of methods comprising administering an unspecified “therapeutically effective amount” of Cx43 protein (or vector encoding Cx43) to an unspecified subject having a functionally defined cancer within the scope of claim 1, along with an unspecified amount of dabrafenib, via an unspecified administration route (i.e., oral, subcutaneous, rectal, etc.), has been deemed obvious in view of the prior art as applied below. Per MPEP § 803.02(III)(A),
Following election, the Markush claim will be examined fully with respect to the elected species and further to the extent necessary to determine patentability. Note that where a claim reads on multiple species, only one species needs to be taught or suggested by the prior art in order for the claim to be anticipated or rendered obvious...
If the Markush claim is not allowable, the provisional election will be given effect and examination will be limited to the Markush claim and claims to the elected species, with claims drawn to species patentably distinct from the elected species held withdrawn from further consideration.
Accordingly, claims 1-6 and 13-14 are rejected in view of the originally elected species and claims that do not read upon the originally elected species are withdrawn.
Claims 8-12 and 16 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 1/28/2026.
Claims 7 and 15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 1/28/2026.
Claims 1-6 and 13-14 are presently considered.
Priority
The priority claim to EP20382883.5 (filed 10/06/2020) is acknowledged.
Information Disclosure Statement
No IDS has been filed at this time.
Claim Interpretation
For purposes of examination, the claim scope has been interpreted as set forth below per the guidance set forth at MPEP § 2111. If Applicant disputes any interpretation, Applicant is invited to unambiguously identify any alleged misinterpretations or specialized definitions in the subsequent response to the instant action. Applicant is advised that a specialized definition should be properly supported and specifically identified (see, e.g., MPEP § 2111.01(IV), describing how Applicant may act as their own lexicographer).
Claim 1 is representative of the pending claim scope, directed to methods, and the applicable claim interpretation is discussed below.
The preamble statement “of treating cancer in a subject in need thereof” is understood to be fully satisfied by the performance of the active method step, namely “administering to the subject in need thereof a therapeutically effective amount of Connexin 43”.
Scope of different cancers encompassed by the claim: The actual types of cancer included or excluded by the phrase “wherein the cancer is characterized by the activation of a mitogen-activated protein kinase (MAPK) selected from the group consisting of: BRAF, RAS, MEK, and ERK” is unknown and undefined on record; rather the types of cancer are only exemplified (see, e.g., Spec. filed 4/06/2023 at 2 at lines 15-21, 3 at final two lines, claims 1 and 3). It is the Examiner’s understanding that the Specification alleges that the “cancer types characterized by the activation of MAPK are well-established” and refers to Dhillon3 in support of this statement (see, e.g., Spec. filed 4/06/2023 at 2 at lines 15-21), rather than simply enumerating the types of cancers treatable by the claimed method. This is problematic because Dhillon does not appear to explain or define what specific types of cancer are included or excluded by the “wherein” clause of instant claim 1 (see, e.g., Dhillon at title, abs, Fig. 1 on 3280, passim). Rather, Dhillon identifies that multiple “MAPK pathways” are not understood (see, e.g., Dhillon at Fig. 1, showing “?” in multiple boxes; see also Dhillon at Fig. 2 on 3280), and concludes that that
The role of MAPKs in cancer is as pleiotropic as cancer itself. Often we are presented with contradictory findings, which we cannot explain. However, on occasions where such discrepancies could be resolved it usually turned out that they were two sides of the same coin. Most mechanisms can protect or harm depending on the context and strength of activation . . . . In either case there should be underlying rules, which we have yet learn to decipher in order to talk cancer cells into resigning.
(see, e.g., Dhillon at 3286 at col II at § Outlook).
Accordingly, Dhillon provides no clear guidance for the metes and bounds of the “wherein” clause that reasonably informs artisans of what cancers are included or excluded by the pending claim scope. Notably, Bonacquisti4 reasonably suggests that increasing Cx43 levels could treat some cancers but make other cancers worse (see, e.g., Bonacquisti at 441 at Table 1; see also id. at 440 at col I at § 3, noting that “Aberrant Cx43 expression, both up- and downregulation, can contribute to cancer development and progression”). For purposes of applying prior art, the phrase is understood to include the specific types of cancer enumerated at dependent claim 3 (i.e., melanoma, colon cancer, lung cancer, or breast cancer).
“Comprising” is an open-ended transitional term (see, e.g., MPEP § 2111.03(I)), wherein additional steps or components are not excluded. However, “‘[c]omprising’ is a term of art used in claim language which means that the named elements are essential” (see, e.g., id.; see also Genentech, Inc. v. Chiron Corp., 112 F.3d 495, 501, 42 USPQ2d 1608, 1613 (Fed. Cir. 1997)).
“Subject in need thereof” is undefined on record, and therefore it is unclear if the claim scope includes prophylactic treatment of people at risk of cancer, or if it requires a diagnosis of cancer. This is pertinent because the applicable patient population “in need” of prophylactic treatment would be substantially larger than the patient population diagnosed with a specific type of cancer.
The dosages encompassed by the phrase “therapeutically effective amount” are functionally defined in the specification as follows:
By "therapeutically effective dose or amount" of a composition comprising the cell suspension of the invention is intended an amount that, when administered as described herein, brings about a positive therapeutic response in a subject having cancer. The exact amount required will vary from subject to subject, depending on the age, and general condition of the subject, the severity of the condition being treated, mode of administration, and the like.
(see, e.g., Spec. filed 4/06/2023 at 5 at final bullet).
Because the term is a functionally defined term, and the “exact amount” will “vary from subject to subject”, it is unknown what amount of Connexin 43 is “therapeutically effective” or not in any particular patient population. This is pertinent because Bonacquisti5 teaches that “Aberrant Cx43 expression, both up- and downregulation, can contribute to cancer development and progression” (see, e.g., Bonacquisti at 440 at col I at § 3, emphasis added), and identifies that some types of cancers are treated by reducing Cx43 expression, while others are treated by increasing Cx43 expression (see, e.g., Bonacquisti at 441 at Table 1 and Table 2). Accordingly, in the absence of clear guidance regarding what does or does not constitute a “therapeutically effective amount” for a particular treatment of a particular cancer, an artisan would not understand that the metes and bounds of the instant claim scope might be.
The structure(s) encompassed by “Connexin 43” is/are not defined on record. It is reasonably inferred that the term is used to refer to at least human connexin 436, which has the following polypeptide sequence:
MGDWSALGKLLDKVQAYSTAGGKVWLSVLFIFRILLLGTAVESAWGDEQSAFRCNTQQPGCENVCYDKSFPISHVRFWVLQIIFVSVPTLLYLAHVFYVMRKEEKLNKKEEELKVAQTDGVNVDMHLKQIEIKKFKYGIEEHGKVKMRGGLLRTYIISILFKSIFEVAFLLIQWYIYGFSLSAVYTCKRDPCPHQVDCFLSRPTEKTIFIIFMLVVSLVSLALNIIELFYVFFKGVKDRVKGKSDPYHATSGALSPAKDCGSQKYAYFNGCSSPTAPLSPMSPPGYKLVTGDRNNSSCRNYNKQASEQNWANYSAEQNRMGQAGSTISNSHAQPFDFPDDNQNSKKLAAGHELQPLAIVDQRPSSRASSRASSRPRPDDLEI
In addition to human Cx43, the term “Connexin 43” is also understood to encompass any homologous sequences identified in the art as “Connexin 43”. Cx43 may also be referred to as “Gap junction alpha-1 protein” in the prior art.
Dabrafenib (a.k.a., CAS NO: 1195765-45-7, GSK2118436A, GSK2118436, GSK-2118436, QGP4HA4G1B, among other names), has the following structure:
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Dabrafenib is known in the art for use in treating multiple types of cancer (see, e.g., US2013/0172378 A1 at claims 5-6, noting that Compound “(II)” is Dabrafenib).
Claim 5 is understood to read upon the elected species, wherein the inhibitor is Dabrafenib, and wherein administration may be made at any time.
Additional claim interpretations are set forth below.
Drawings
The drawings are objected to under 37 CFR 1.83(a) because they fail to show colors as described in the specification (see, e.g., Spec. filed 4/06/2023 at page 8 at line 3 and page 25 at line 5 referring to “orange” in Figure 3c, page 8 at lines 11 and 8 and page 25 at line 5 and line 20 referring to “blue” in Figure 3c and 3e; page 8 at line 7 referring to “red”; page 8 at line 11 and 25 at line 20 referring to “green” at Figure 3e; these examples are not exhaustive given the length of the specification, and Applicant’s help is requested in identifying additional references to colors. Any structural detail that is essential for a proper understanding of the disclosed invention should be shown in the drawing. MPEP § 608.02(d). Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Claim Rejections
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 1-6 and 13-14 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 1 recites “treating cancer in a subject in need thereof”, which renders the claim scope indefinite because both “treating” and “a subject in need thereof” are each undefined on record, and therefore it is unclear if the claim includes or excludes prophylactic treatments of patients at risk of having melanoma, colon cancer, lung cancer, breast cancer, or another form of cancer encompassed by instant claim 1. This is pertinent because close prior art exists, wherein Cx43 is delivered to subjects to treat other non-cancer conditions (see, e.g., Roell7 at title, abs, 8-9 at bridging ¶; see also Fernandes8 at title, abs; see also US 7094201B1 at title, abs, claims), and it is unclear if these patients are included or excluded by the pending claim scope. More specifically, if “treating cancer in a subject in need thereof” requires a patient to actually have or be diagnosed with cancer, then such prior art is excluded from the instant claim scope; however, if the phrase “treating cancer in a subject in need thereof” broadly encompasses prophylactic treatment in patients at risk of developing cancer, then such prior art may read upon the instant claims, because such patients are reasonably “at risk” and would benefit from prophylactic treatments. For purposes of applying prior art, the claim scope is understood to include the treatment of at least patients having the specific types of cancer enumerated at dependent claim 3 (i.e., melanoma, colon cancer, lung cancer, or breast cancer).
Claim 1 recites the phrase “therapeutically effective amount of Connexin 43”, which is undefined on record and renders the claim scope indefinite as explained herein. Per MPEP § 2173.05(g), “the use of functional language in a claim may fail ‘to provide a clear-cut indication of the scope of the subject matter embraced by the claim’ and thus be indefinite. Here, the specification identifies that the term is functionally defined as an “intended” amount that “when administered . . brings about a positive therapeutic response”, but admits that “[t]he exact amount will vary from subject to subject” (see, e.g., Spec. filed 4/06/2023 at 5 at final bullet). Accordingly, the phrase “therapeutically effective amount of Connexin 43” is a functional limitation based upon an “intended” and hoped-for result, wherein the amount admittedly varies in an unknown manner. This renders the claim scope indefinite in the instant case because Bonacquisti9 teaches that “Aberrant Cx43 expression, both up- and downregulation, can contribute to cancer development and progression” (see, e.g., Bonacquisti at 440 at col I at § 3, emphasis added), and identifies that some types of cancers are treated by reducing Cx43 expression, while others are treated by increasing Cx43 expression (see, e.g., Bonacquisti at 441 at Table 1 and Table 2; see also, Ableser10 at 1592 at 1st ¶ explaining that Cx43 can act as either a tumor suppressor or a tumor enhancer). Accordingly, it is unclear what amounts are therapeutically advantageous to any particular patient population, and which amounts would be detrimental to any particular patient population. Per MPEP § 2173.05(g), this is an indefinite usage of functional language because
[T]he use of functional language in a claim may fail "to provide a clear-cut indication of the scope of the subject matter embraced by the claim" and thus be indefinite….For example, when claims merely recite a description of a problem to be solved or a function or result achieved by the invention, the boundaries of the claim scope may be unclear. . . . the Supreme Court explained that a vice of functional claiming occurs "when the inventor is painstaking when he recites what has already been seen, and then uses conveniently functional language at the exact point of novelty"
(see, e.g., MPEP § 2173.05(g), emphasis added).
Accordingly, it is unclear what actual amounts of Cx43 are “therapeutically effective” and within the scope of the instant claim for treating a particular patient population, and what amounts are not “therapeutically effective” to a particular patient population, and therefore excluded by the instant claim scope. This issue is compounded by the ambiguous patient population being treated (see preceding paragraph regarding prophylactic usage; see also following paragraph addressing “wherein” clause). Accordingly, the phrase “therapeutically effective amount of Connexin43” is an ill-defined and ill-described functional limitation, close prior art exists (see rejections, below), and because of the ambiguous metes and bounds of the claim scope, an artisan would be unable to unambiguously distinguish infringing from non-infringing prior art. For purposes of applying prior art, the claim scope is understood to include the treatment of at least patients having the specific types of cancer enumerated at dependent claim 3 (i.e., melanoma, colon cancer, lung cancer, or breast cancer), wherein any amount identified as having a therapeutic benefit is reasonably inferred to read upon the pending claim scope.
Claims 1, 2, and claim 13 attempt to define a genus of cancers by reference to a functional limitation (i.e., “wherein the cancer is characterized by the activation of a mitogen-activated protein kinase (MAPK) selected from the group consisting of: BRAF, RAS, MEK, and ERK” at claims 1 and 13; “wherein the cancer is characterized by the activation of BRAF or NRAS” at claim 2), which do not correspond to a clear structure/function relationship on record the reasonably identifies cancers included or excluded by the instant claim scope. The actual types of cancer included or excluded by these functional limitations are unknown and undefined on record. Rather the types of cancer are only exemplified (see, e.g., Spec. filed 4/06/2023 at 2 at lines 15-21, 3 at final two lines, claims 1 and 3). Rather than simply and unambiguously enumerating the exact types of cancers treatable by the claimed method, it is the Examiner’s understanding that the Specification simply alleges that the “cancer types characterized by the activation of MAPK are well-established” and refers to Dhillon11 in support of this statement (see, e.g., Spec. filed 4/06/2023 at 2 at lines 15-21). However, Dhillon does not appear to explain or define what specific types of cancer are included or excluded by the “wherein” clause of instant claim 1 (see, e.g., Dhillon at title, abs, Fig. 1 on 3280, passim). Rather, Dhillon identifies that multiple “MAPK pathways” are not understood (see, e.g., Dhillon at Fig. 1, showing “?” in multiple boxes; see also Dhillon at Fig. 2 on 3280), and concludes that that
The role of MAPKs in cancer is as pleiotropic as cancer itself. Often we are presented with contradictory findings, which we cannot explain. However, on occasions where such discrepancies could be resolved it usually turned out that they were two sides of the same coin. Most mechanisms can protect or harm depending on the context and strength of activation . . . . In either case there should be underlying rules, which we have yet learn to decipher in order to talk cancer cells into resigning.
(see, e.g., Dhillon at 3286 at col II at § Outlook).
Accordingly, Dhillon provides no clear guidance for the metes and bounds of the “wherein” clause that reasonably informs artisans of what cancers are included or excluded by the pending claim scope. This is pertinent because close prior art exists, such as Hattori12, which teaches that non-viral delivery of Cx43 via nanoparticles can inhibit in vivo nasopharyngeal tumor growth (see, e.g., Hattori at title, abs, Fig. 5 on 1435, Fig. 6 on 1436), but it is unclear if such cancers are included or excluded by the functional definition set forth in the “wherein” clause. Per MPEP § 2173.05(g), this is an indefinite usage of functional language because
[T]he use of functional language in a claim may fail "to provide a clear-cut indication of the scope of the subject matter embraced by the claim" and thus be indefinite….For example, when claims merely recite a description of a problem to be solved or a function or result achieved by the invention, the boundaries of the claim scope may be unclear. . . . the Supreme Court explained that a vice of functional claiming occurs "when the inventor is painstaking when he recites what has already been seen, and then uses conveniently functional language at the exact point of novelty"
(see, e.g., MPEP § 2173.05(g), emphasis added).
Here, the functional “wherein” clause merely attempts to define a genus of cancers that Cx43 administration could allegedly be utilized to treat, but such functional limitation does not actually correspond to a clear, well-defined genus of specific types of cancers. This renders the claim scope indefinite because it is unclear what actual cancer types are included or excluded from the claim scope by this functional language, and therefore the claim does not satisfy the “primary purpose” of 35 USC § 112(b), which is to “to ensure that the scope of the claims is clear so the public is informed of the boundaries of what constitutes infringement of the patent”, because an artisan attempting to treat an unexemplified type of cancer would not be clearly informed of whether or not they had infringed the instant claim scope or not. For purposes of applying prior art, the claim scope is understood to include the treatment of at least patients having the specific types of cancer enumerated at dependent claim 3 (i.e., melanoma, colon cancer, lung cancer, or breast cancer), wherein any amount identified as having a therapeutic benefit is reasonably inferred to read upon the pending claim scope.
Claim 4 recites a functionally defined genus, namely “inhibitor of a mitogen-activated protein kinase (MAPK) selected from the group consisting of: BRAF, RAS, MEK, and ERK”, which renders the claim scope indefinite because the functional language fails to correspond to a structure/function relationship permitting an artisan to meaningfully identify the inhibitors encompassed by the claim. For example, Hattori13 teaches that non-viral delivery of Cx43 via nanoparticles in combination with 4-phenylbutyrate (4-PB) can inhibit in vivo nasopharyngeal tumor growth (see, e.g., Hattori at title, abs, Fig. 5 on 1435, Fig. 6 on 1436), but it is unclear if 4-PB is considered an inhibitor of, for example ERK, or not, and no structure/function guidance of record permitting an artisan to distinguish what structures are included or excluded from the scope of the functional limitation is provided on record. Per MPEP § 2173.05(g), this is an indefinite usage of functional language because
[T]he use of functional language in a claim may fail "to provide a clear-cut indication of the scope of the subject matter embraced by the claim" and thus be indefinite….For example, when claims merely recite a description of a problem to be solved or a function or result achieved by the invention, the boundaries of the claim scope may be unclear. . . . the Supreme Court explained that a vice of functional claiming occurs "when the inventor is painstaking when he recites what has already been seen, and then uses conveniently functional language at the exact point of novelty"
(see, e.g., MPEP § 2173.05(g), emphasis added).
Here, the functional “wherein” clause merely attempts to define a genus that achieves an outcome that Applicant hopes and desires for the invention to achieve, without actually describing a consensus motif or common structure shared by all such inhibitors responsible for achieving the hoped-for and desired functionality. Therefore the claim does not satisfy the “primary purpose” of 35 USC § 112(b), which is to “to ensure that the scope of the claims is clear so the public is informed of the boundaries of what constitutes infringement of the patent”, because an artisan attempting to treat a cancer using a compound, such as 4-phenylbutyrate (4-PB) as disclosed by Hattori, would not be clearly informed of whether or not they had infringed the instant claim scope or not. For purposes of applying prior art, the claim scope is understood to include the treatment of at least patients having the specific types of cancer enumerated at dependent claim 3 (i.e., melanoma, colon cancer, lung cancer, or breast cancer), by administering Cx43 in combination with Dabrafenib.
Claims 2-6 and 14 depend directly or indirectly from indefinite base claims, and fail to clarify the indefiniteness of the base claims. Accordingly, claims 2-6 and 14 are rejected for the reasons applicable to claims 1 and 13, above.
Claims 1-6 and 13-14 are rejected.
Claim Rejections - 35 USC § 112(a), Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-6 and 13-14 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.
Brief Statement of the Issue(s)
The claims are directed to methods of “treating cancer” that depend upon functional limitations that are ill-described on record. It is unclear if “treating” includes prophylactic treatment and prevention, or something narrower. If it unclear what types of cancer can or cannot be successfully treated using the method. Finally, the dosage is defined using an ambiguous functional limitation.
Claim Scope
Claims 1 and 13 are representative of the pending claims scope.
The applicable claim interpretations have been set forth above under 35 USC 112(b) and in a separate claim interpretation section. Those discussions are incorporated herein.
It is unclear if the claimed methods encompass treatment of hundreds of types of cancers, or perhaps only less than a dozen subtypes (see, e.g., discussion above under 35 USC 112(b), incorporated herein).
It is unclear if the claimed methods encompass prophylactic treatment of patients at risk of cancer, or if the claims are limited only to treatments of diagnosed patients (see, e.g., discussion above under 35 USC 112(b), incorporated herein).
It is unclear what does or does not constitute a “therapeutically effective amount” of Cx3 for any particular cancer type (see, e.g., discussion above under 35 USC 112(b), incorporated herein).
It is unclear what does or does not constitute an “inhibitor” as defined by the functional limitation set forth at instant claim 4 (see, e.g., discussion above under 35 USC 112(b), incorporated herein).
Actual Reduction to Practice
Zero embodiments of the claimed invention were reduced to practice, because zero examples of any in vivo administration was tested or disclosed on record.
Assessment of whether disclosed species are representative of the claimed genus
MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus (see, e.g., MPEP § 2163(II)(3)(a), MPEP §2163.03(V)). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. In this case, the claims encompass a vast and highly varied genus of methods of treating an unknown number of different cancers and cancer subtypes, by administering (via any known route, e.g., oral, subcutaneous, subdermal, sublingual, intraocular, vaginal, depot, implant, etc.) an unknown “therapeutically effective amount” of a Cx43 protein (polynucleotide encoding a peptide), but zero embodiments of the claimed methods were actually reduced to practice wherein a specific patient population was administered any form of Cx43 via any route at any dosage, and thereby “treated” in any manner.
Although the MPEP does not define what constitutes a sufficient number of representative species, the Courts have indicated that the disclosure of two species within a subgenus did not describe that subgenus. In re Gostelli, 872 F.2d at 1012, 10 USPQ2d at 1618. Similarly, the disclosure of zero examples of the claimed invention does not provide sufficient disclosure to satisfy the written description requirement for the instantly claimed genus.
Identifying characteristics of the genus
In the absence of a reduction to practice of a representative number of species, the written description requirement for a claimed genus may be satisfied by disclosure of relevant, identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.
It is unclear what types of cancers can be treated by the claimed methods, and which types of cancers are excluded from the scope of claim 1: The prior art teaches that Cx43 can act as either a tumor suppressor or a tumor enhancer (see, e.g., Ableser14 at 1592 at 1st ¶). Therefore, because Cx43 can actually “enhance” some types of cancer, a basic, threshold question is simply “What types of cancers are included or excluded by the pending claim scope?” Claims 1-2 and 13 attempt to address this reference to a functional limitation (e.g., namely “wherein the cancer is characterized by the activation of a mitogen-activated protein kinase (MAPK) selected from the group consisting of: BRAF, RAS, MEK, and ERK” at claims 1 and 13, “wherein the cancer is characterized by the activation of BRAF or NRAS” at claim 2), but these “wherein” clauses fail to meaningfully correspond to any clear structure/function relationship of record. Accordingly, other than the explicitly claimed and exemplified cancer types (see, e.g., Spec. filed 4/06/2023 at 2 at lines 15-21, 3 at final two lines, claims 1 and 3)., it is prima facie unclear what other types of cancer are included or excluded by such claim language. Rather than enumerate applicable cancer types, the original disclosure alleges that the “cancer types characterized by the activation of MAPK are well-established” and refers to Dhillon15 in support of this statement (see, e.g., Spec. filed 4/06/2023 at 2 at lines 15-21). However, Dhillon does not appear to explain or define what specific types of cancer are included or excluded by the “wherein” clause of instant claim 1 (see, e.g., Dhillon at title, abs, Fig. 1 on 3280, passim). Rather, Dhillon identifies that multiple “MAPK pathways” are not understood (see, e.g., Dhillon at Fig. 1, showing “?” in multiple boxes; see also Dhillon at Fig. 2 on 3280), and concludes that that
The role of MAPKs in cancer is as pleiotropic as cancer itself. Often we are presented with contradictory findings, which we cannot explain. However, on occasions where such discrepancies could be resolved it usually turned out that they were two sides of the same coin. Most mechanisms can protect or harm depending on the context and strength of activation . . . . In either case there should be underlying rules, which we have yet learn to decipher in order to talk cancer cells into resigning.
(see, e.g., Dhillon at 3286 at col II at § Outlook).
Accordingly, it is unclear if the “wherein” clause is intended to encompass all possible types of cancer, or only some undisclosed subtypes of cancers that include those enumerated at instant claim 3. As an example, Hattori16 teaches that non-viral delivery of Cx43 via nanoparticles in combination with 4-phenylbutyrate (4-PB) can inhibit in vivo nasopharyngeal tumor growth (see, e.g., Hattori at title, abs, Fig. 5 on 1435, Fig. 6 on 1436), but it is unclear if this type of cancer is excluded from the scope of instant claim 1 by the functional limitation at claims 1 and 13, or not. Rather, an artisan is left with the burden of newly discovering and characterizing the entire MAPK pathway for each type of cancer treated, to determine whether or not infringement of the instant claims may have occurred or not. Therefore, in view of the instant disclosure, it is unclear what the patient population may be, because it is prima facie unknown what types of cancers are included or excluded by the functional language of the “wherein” clause.
It is unclear what types of “treatment” are included by the claimed methods: Another basic, threshold question is simply “What is included in ‘treating’? Prophylactic treatment?” It is unclear if the claims include or exclude prophylactic treatments of patients at risk of having melanoma, colon cancer, lung cancer, breast cancer, or another form of cancer encompassed by instant claims 1 or 13. This is pertinent because close prior art exists, wherein Cx43 is delivered to subjects to treat other non-cancer conditions (see, e.g., Roell17 at title, abs, 8-9 at bridging ¶; see also Fernandes18 at title, abs; see also US 7094201B1 at title, abs, claims), and it is unclear if these patients are included or excluded by the pending claim scope, because such prior art would presumably read upon the claim scope if prophylactic treatment was included by the pending claim scope, since such prior art patients are in need of preventative and prophylactic treatments for melanoma, breast cancer, colon cancer, and lung cancer. Accordingly, it is unclear “treatment” encompasses prophylactic treatment or prevention, or if “treatment” in the instant claims are limited to patients diagnosed with a cancer within the scope of claim 1 or 13.
It is unclear what does or does not constitute a “therapeutically effective amount of Connexin 43”: Claims 1 and 13 recite and require a “therapeutically effective amount of Connexin 43”, which is not defined, but described on record using functional language, identifying that the phrase refers to an “intended” amount that “when administered . . brings about a positive therapeutic response”, wherein the “positive” response is not identified, and wherein the disclosure admits that “[t]he exact amount will vary from subject to subject” (see, e.g., Spec. filed 4/06/2023 at 5 at final bullet). This is problematic because the prior art teaches that Cx43 can act as either a tumor suppressor or a tumor enhancer (see, e.g., Ableser19 at 1592 at 1st ¶; see also Bonacquisti at 440 at col I at § 3, explaining that “Aberrant Cx43 expression, both up- and downregulation, can contribute to cancer development and progression”). This is relevant because if the wrong among of Cx43 is administered to the wrong patient, it would be expected to make the cancer worse rather than better (see id). Accordingly, the “therapeutically effective amount of Connexin 43” is critically important, but the instant disclosure merely uses functional language to recite a description of a problem to be solved or a function to be achieved by the invention, but without actually providing clear guidance as to what actual amounts in any particular patient population are “therapeutically effective” or not, as required by the instant claims. Furthermore, Cx43 is routinely administered as small doses to cancer patients in the form of blood transfusions, which are frequently utilized to treat cancer patient in need thereof (see, e.g., Cata at title, abs, Table 1 at 3; see, e.g., Vaiyapuri at abs, 2480 at col II at 3rd full ¶, Fig. 1 on 2481, noting that Cx43 is understood to be present in blood products such as platelets present in blood transfusions). However, it is unclear if blood transfusions read upon the instant claims or not, because it is unclear if the amount of Cx43 present in a blood transfusion constitutes a “therapeutically effective amount” within the scope of the instant claims or not.
It is unclear what does or does not constitute an “inhibitor” at claim 4: Claim 4 recites a functionally defined genus, namely “inhibitor of a mitogen-activated protein kinase (MAPK) selected from the group consisting of: BRAF, RAS, MEK, and ERK”, which does not correspond to a structure/function relationship of record permitting an artisan to identify, a priori, what compounds do or do not satisfy the functional limitation. In the absence of guidance, an artisan is simply left to guess, at or otherwise be burdened to newly discover, what compounds are included or excluded by the functional limitation. As a single example, Hattori20 teaches that non-viral delivery of Cx43 via nanoparticles in combination with 4-phenylbutyrate (4-PB) can inhibit in vivo nasopharyngeal tumor growth (see, e.g., Hattori at title, abs, Fig. 5 on 1435, Fig. 6 on 1436), but it is unclear if 4-PB is considered an inhibitor of, for example ERK, or not, and no structure/function guidance of record permitting an artisan to distinguish what structures are included or excluded from the scope of the functional limitation is provided on record. Per MPEP § 2173.05(g), this is an indefinite usage of functional language because
[T]he use of functional language in a claim may fail "to provide a clear-cut indication of the scope of the subject matter embraced by the claim" and thus be indefinite….For example, when claims merely recite a description of a problem to be solved or a function or result achieved by the invention, the boundaries of the claim scope may be unclear. . . . the Supreme Court explained that a vice of functional claiming occurs "when the inventor is painstaking when he recites what has already been seen, and then uses conveniently functional language at the exact point of novelty"
(see, e.g., MPEP § 2173.05(g), emphasis added).
Here, the functional “wherein” clause merely attempts to define a genus that achieves an outcome that Applicant hopes and desires for the invention to achieve, without actually describing a consensus motif or common structure shared by all such inhibitors responsible for achieving the hoped-for and desired functionality. Therefore the claim does not satisfy the “primary purpose” of 35 USC § 112(b), which is to “to ensure that the scope of the claims is clear so the public is informed of the boundaries of what constitutes infringement of the patent”, because an artisan attempting to treat a cancer using a compound, such as 4-phenylbutyrate (4-PB) as disclosed by Hattori, would not be clearly informed of whether or not they had infringed the instant claim scope or not.
At best, the originally filed disclosure provides evidence that within an in vitro cell study showing that Cx43 transfected cells exhibit some results in vitro, but it is unclear how such results translate to any treatment in vivo as instantly claimed. It is the Examiner’s position that such data pertaining to the instantly claimed invention does not appear to be substantially more than what was already known in the prior art. Specifically, Cx43 treatments of in vitro and in vivo melanoma systems were already known in the prior art as evidenced by Ableser et al21 (see, e.g., Ableser at title, abs, 1593 at col I-II at bridging ¶, 1594 at col II at 2nd full ¶, 1595 at col I at 3rd full ¶, 1595-1596 at bridging ¶, 1597 at col II at 1st full ¶ noting that “Here we show that Cx43, and not Cx26, is an effective tumor suppressor in melanomas”, 1600-1601 at bridging ¶; see also Ableser at 1597 at col I-II at bridging ¶, 1597 at col II at 1st full ¶, 1600-1601 at bridging ¶). Critically, Ableser was published approximately 6 years prior to the filing of the instant Application, but the discovery of Ableser has not been sufficient to translate to treatment, in vivo, of other types of cancers within the scope of instant claim 1 and 13, due in part to the fact that Cx43 can act as a tumor enhancer if used incorrectly (see, e.g., Ableser at 1592 at col I at 1st ¶). However, the instant disclosure fails to address this art-recognized issue, but instead appears to merely gloss over such required descriptions by relying upon functional limitations that merely recite what the Applicant hopes and desires to achieve, without actually providing a single, working example of the claimed invention and without actually addressing the concerns raised by the prior art.
Accordingly, zero working examples, in vivo, were actually disclosed on record; the originally filed disclosure does not appear to disclose substantially more than what was already known in the prior art (see, e.g., Ableser, discussed above); the originally filed disclosure fails to provide structure/function relationships for multiple functional limitations; and the originally filed disclosure fails to address the concerns of the prior art regarding Cx43 acting as either a tumor suppressor or a tumor enhancer, such as by clearly identifying what exact cancers could be treated by specific dosages of Cx43 in combination with specific inhibitors, and which structures and concentrations are excluded.
Predictability in the Art
Although the level of skill in the art is high, the predictability in the clinical arts is low due to the complexity of biological systems, differences in patient populations, differences between species of cancer and cancer subtypes, concentration effects, administration route effects, dosage frequency effects, and arbitrary metrics defining “success” or “failure” of a treatment among artisans. Specifically, an artisan would not be able to predict or identify, a priori, and in the absence of any guidance, the minimal, common dosages required to constitute a “therapeutically effective amount” that would not actually make a cancer worse; be able to identify which cancers were included or excluded by the “wherein” clause at instant claims 1 and 13; or otherwise identify what structures did or did not inhibit a portion of the MAPK pathway.
Accordingly, in the absence of (i) sufficient structure/function teachings identifying a “therapeutically effective amount” of Cx43, (ii) sufficient identifying information to identify what cancers are included or excluded by the “wherein” clause at claims 1 and 13, (iii) sufficient description to know whether or not the claim scope encompasses prevention and/or prophylactic treatments, and (iv) sufficient structure/function teachings permitting an artisan to identify whether or not something constituted an “inhibitor”, an artisan would not reasonably conclude that Applicant possessed the full scope of the broad and highly varied genus of methods recited and encompassed by instant claims 1-6 and 13-14.
Conclusion
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."). The courts have stated that “merely drawing a fence around a perceived genus is not a description of the genus. One needs to show that one has truly invented the genus, i.e., that one has conceived and described sufficient representative species encompassing the breadth of the genus. Otherwise, one has only a research plan, leaving it to others to explore the unknown contours of the claimed genus” (see, e.g., AbbVie v. Janssen, 111 USPQ2d 1780 (Fed. Cir. 2014) at 1789). Likewise, in the instant case, the claims are directed to methods of treating a functionally defined genus of cancers, by administering functionally defined amounts of Cx43 in combination with a functionally defined inhibitor, to achieve some outcome identifiable as a “treatment”, but the disclosure fails to provide sufficient structure/function relationships to permit an artisan to reasonably identify what embodiments do or do not fall within the scope of the instant claims, but rather the claims only identify generically “goals [Applicant] hope the claimed invention achieves”, but have left it completely to others to actually invent and discover the specifics of the methods Applicant has attempted to claim, and have failed to address concerns in the prior art, including the fact that Cx43 may act as a tumor enhancer if utilized at the wrong dosage or cancer type.
The courts have held that a claim to a therapeutic method requiring administration of an “effective” amount of a compound at specific dosage range set forth in the disclosure for the treatment of a broad array of disorders failed to satisfy the Written Description Requirement because the disclosure addressed only “basic research and broad []dosage ranges”, but did not establish possession of a “therapeutically effective [] dose at the time of filing” (see, e.g., Biogen Int'l GmbH v. Mylan Pharm. Inc., 18 F.4th 1333, 1343, 2021 U.S.P.Q.2d 1170, 2021 BL 455178, at *8 (Fed. Cir. 2021). The court clarified that although
An inventor need not "prove that a claimed pharmaceutical compound actually achieves a certain result. But when the inventor expressly claims that result, our case law provides that [such] result must be supported by adequate disclosure in the specification.”
See Biogen Int'l GmbH v. Mylan Pharm. Inc., 18 F.4th 1333, 1343 (Fed. Cir. 2021).
The court further explained that
That Biogen later established the therapeutic efficacy of [a known compound at a specific dosage] is of no import to the written-description analysis. What matters for purposes of the inquiry [*1344] in this case is whether, at the time of filing the disclosure—well before the Phase III study even commenced—a skilled artisan could deduce simply from reading the specification that [a known compound at a specific dosage] would be a therapeutically effective treatment for MS. As to this point, the specification's focus on drug discovery and basic research further buttresses the district court's conclusion that the specification lacks an adequate written description to support the [] claims. . . . the law is clear that a patent cannot be awarded for mere theoretical research without more, see Ariad, 598 F.3d at 1353 . The written-description requirement limits patent protection only to individuals who perform the difficult work of producing a complete and final invention featuring all its claimed limitations and publicly disclose the fruits of that effort.
See Biogen Int'l GmbH v. Mylan Pharm. Inc., 18 F.4th 1333, 1344, 2021 U.S.P.Q.2d 1170, 2021 BL 455178, at *9 (Fed. Cir. 2021); emphasis added
Here, like in Biogen, the Specification is directed to basic research without clear clinical data sharing a nexus with the claims because zero embodiments of the claimed invention were actually reduced to practice or discussed with specificity. Furthermore, unlike Biogen, here the claims further attempt to draw a fence around the treatment of numerous possible species of cancers satisfying the ill-defined functional limitation set forth in the “wherein” clauses of claims 1 and 13, without disclosing a clear definition, and further attempt to claim a functionally defined “therapeutically effective amount” without a clear structure/function relationship. Therefore, the instant claims are substantially broader in scope than the claims of Biogen, but the disclosure of the instant Specification appears to provide substantially less guidance than that of the specification at issue in Biogen. Therefore, like Biogen, the instant claims lack written description support because an artisan “simply from reading the specification” could not deduce which concentration would be “therapeutically effective” for the treatment of any particular type of cancer, as presently claimed.
Accordingly, claims 1-6 and 13-14 are rejected.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claims 1-3 are rejected under 35 U.S.C. 102(a)(1) as being clearly anticipated by Ableser et al22.
Claim interpretation: The applicable claim interpretation has been set forth in a preceding section above, and those interpretations are incorporated into the instant rejection. Additional claim interpretations are set forth below.
Regarding instant claims 1-3, Ableser teaches and discloses that Connexin43 reduces melanoma growth in vivo (see, e.g., Ableser at title, abs, 1593 at col I-II at bridging ¶, 1594 at col II at 2nd full ¶, 1595 at col I at 3rd full ¶, 1595-1596 at bridging ¶, 1597 at col II at 1st full ¶ noting that “Here we show that Cx43, and not Cx26, is an effective tumor suppressor in melanomas”, 1600-1601 at bridging ¶), wherein the subject is a chicken embryo (see id), which was administered stably-transfected Cx43-expressing cells (see id), and wherein Cx43 was administered at a therapeutically effective amount sufficient to act as a tumor suppressor and to reduce primary tumor weight (see, e.g., Ableser at 1597 at col I-II at bridging ¶, 1597 at col II at 1st full ¶, 1600-1601 at bridging ¶). Accordingly, the prior art teaches methods of treating melanoma, in vivo, by administering Cx43 at an amount sufficient to achieve a therapeutic benefit.
Accordingly, claims 1-3 are anticipated by the prior art.
Claims 1-3 are rejected under 35 U.S.C. 102(a)(1) as being clearly anticipated by Cata23 as evidenced by Vaiyapuri et al.24
Claim interpretation: The applicable claim interpretation has been set forth in a preceding section above, and those interpretations are incorporated into the instant rejection. Any amount of Cx43 encoding polynucleotide or Cx43 protein is understood to be a “therapeutically effective” amount if a therapeutic benefit is achieved by the administration of a composition comprising any amount of Cx43. Additional claim interpretations are set forth below.
Regarding instant claims 1-3, Cata informs artisans that blood transfusions are utilized to treat cancer patients in need thereof, including lung cancer patients (see, e.g., Cata at title, abs, Table 1 at 3). However, as evidenced by Vaiyapuri, Cx43 is understood to be present in blood products (e.g., platelets) present in blood transfusions (see, e.g., Vaiyapuri at abs, 2480 at col II at 3rd full ¶, Fig. 1 on 2481). Accordingly, patients in need of treatment for lung cancer were necessarily and inherently administered a composition comprising of an amount of Cx43 sufficient to achieve a therapeutic result in combination with other components.
Accordingly, claims 1-3 are rejected.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 and 13-14 are rejected under 35 U.S.C. 103 as being unpatentable over Ableser et al25 as applied to claims 1-3 above, and further in view of US2013/0172378 (Jul. 4, 2013) and Bonacquisti26.
Claim interpretation: The applicable claim interpretation has been set forth in a preceding section above, and those interpretations are incorporated into the instant rejection. Additional claim interpretations are set forth below.
The teachings of the primary reference as applied to claims 1-3 have been discussed above, and those teachings are incorporated herein. In brief, Ableser teaches and discloses that Connexin43 acts as a tumor suppressor in melanoma (see, e.g., Ableser at title, abs, 1597 at col I-II at bridging ¶, 1592 at col I at 1st ¶, 1593 at col I-II at bridging ¶, 1594 at col II at 2nd full ¶, 1595 at col I at 3rd full ¶, 1595-1596 at bridging ¶, 1597 at col II at 1st full ¶ noting that “Here we show that Cx43, and not Cx26, is an effective tumor suppressor”, 1600-1601 at bridging ¶), and identifies that Cx43 was also known in the art to reduce angiogenesis in breast cancer models (see, e.g., Ableser at 1600 at col II at 1st full ¶). Accordingly, Ableser provides guidance informing artisans that Cx43 could be utilized to treat breast cancer and melanoma. Regarding instant claim 13, Ableser identifies that Cx43 could be introduced to cells using a stably transfected expression vector (see, e.g., Ableser at 1593 at col I-II at bridging ¶), and therefore an artisan would readily appreciate that Cx43 could be administered as a protein or as a polynucleotide encoding and capable of expressing the protein.
The primary reference differs from instant claims 3-6 and 13-14 as follows: Although the primary reference reports that stably transfected vectors expressing Cx43 acts as a tumor suppressor in melanoma and that Cx43 can treat breast cancer, the primary reference does not teach or disclose the use of Cx43 in combination with a “BRAF or a MEK inhibitor” such as dabrafenib.
Regarding instant claims 1-6, 13-14, and the treatment of cancers by administering Dabrafenib, US’378 teaches, discloses, and claims methods of treating cancers in humans by administering a “therapeutically effective amount” of
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(see, e.g., US’378 at claims 5-7, noting that Formula (II), shown above, is Dabrafenib), wherein the cancer may be at least melanoma or breast cancer (see, e.g., US’378 at claims 6-7, ¶[0033] noting that Dabrafenib is also referred to as “Compound B”), and wherein the “therapeutically effective amount” is understood to be from about 10 mg to 600 mg (see, e.g., US’378 at claims 6-7, ¶¶[0033], [0100], noting that Dabrafenib is also referred to as “Compound B”). Accordingly, methods of administering dabrafenib to humans for the treatment of melanoma and/or breast cancer were already known in the prior art.
In addition, Bonacquisti informs artisans that Cx43 expression is known and expected to increase cellular permeability to chemotherapeutics (see, e.g., Bonacquisti at 442 at col I-II at §§ 4.3), explaining that “Cx43 overexpression may be exploited for targeted drug delivery to cancer cells via enhanced drug permeability” (see id). Accordingly, an artisan would readily expect and predict that Cx43 expression could improve prior art methods of treating cancers by administering chemotherapeutics, such as those disclosed by US’378.
Therefore, it would have been obvious to one of ordinary skill in the art, either before the effective filing date of the claimed invention (AIA ) or otherwise at the time the invention was made (pre-AIA ), to arrive at the instantly claimed invention in view of the prior art for at least the following reason(s): Per MPEP § 2144.06(I), "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted). Likewise, here, the prior art teaches and discloses Cx43 and Dabrafenib for the very same purpose, namely to treat melanoma and/or breast cancer, and therefore combining such prior art elements together to form a combined method for treating melanoma and/or breast cancer is prima facie obvious because the idea flows logically from their having been individually taught in the prior art (see, e.g., MPEP § 2144.06(I)). In addition, or alternatively, the invention is the obvious application of the known techniques of utilizing Cx43 as a tumor suppressor as taught by the primary reference and to improve chemotherapeutic permeability as taught by Bonacquisti, to the methods of treating melanoma and breast cancer by administering Dabrafenib as taught and claimed by US’378, which would predictably yield an improved method of treating melanoma and breast cancer wherein Cx43 acts as a tumor suppressor, angiogenesis suppressor, and as a chemotherapeutic permeability enhancer, exactly as taught and suggested by the prior art (see, e.g., MPEP §§ 2143(I)(C), (D), (G)).
No evidence of unexpected results commensurate in scope with the requirements of MPEP §§ 716, 716.01, and 716.02 have been placed on record to date.
Furthermore, there would be a reasonable expectation of success because the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)). Furthermore, it is well-within the ordinary skill in the art to make and use known compounds in known methods to obtain the results taught and suggested by the prior art.
Accordingly, claims 1-6 and 13-14 are rejected.
Claims 1-6 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Cata27 as evidenced by Vaiyapuri et al.28 as applied to claims 1-3 above, and further in view of US2013/0172378 (Jul. 4, 2013).
Claim interpretation: The applicable claim interpretation has been set forth in a preceding section above, and those interpretations are incorporated into the instant rejection. Additional claim interpretations are set forth below.
The teachings of the primary reference as applied to claims 1-3 have been discussed above, and those teachings are incorporated herein. As discussed above, Cx43 is necessarily delivered to cancer patients upon blood transfusions (see, e.g., Cata at title, abs, Table 1 at 3), because Cx43 is present in blood and blood products (see, e.g., Vaiyapuri at abs, 2480 at col II at 3rd full ¶, Fig. 1 on 2481). Because a therapeutically beneficial effect is achieved by a blood transfusion, Cx43 is inferred to inherently be present in a therapeutically effective amount.
The primary reference differs from instant claims 3-6 and 13-14 as follows: Although the primary reference discloses that blood transfusions may be utilized with cancer patients as needed, the primary reference does not teach or disclose the use of Cx43 in combination with a “BRAF or a MEK inhibitor” such as dabrafenib.
Regarding instant claims 1-6, 13, and the treatment of cancers by administering Dabrafenib, US’378 teaches, discloses, and claims methods of treating cancers in humans by administering a “therapeutically effective amount” of
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(see, e.g., US’378 at claims 5-7, noting that Formula (II), shown above, is Dabrafenib), wherein the cancer may be at least melanoma or breast cancer (see, e.g., US’378 at claims 6-7, ¶[0033] noting that Dabrafenib is also referred to as “Compound B”), and wherein the “therapeutically effective amount” is understood to be from about 10 mg to 600 mg (see, e.g., US’378 at claims 6-7, ¶¶[0033], [0100], noting that Dabrafenib is also referred to as “Compound B”). Accordingly, methods of administering dabrafenib to humans for the treatment of melanoma and/or breast cancer were already known in the prior art.
Therefore, it would have been obvious to one of ordinary skill in the art, either before the effective filing date of the claimed invention (AIA ) or otherwise at the time the invention was made (pre-AIA ), to arrive at the instantly claimed invention in view of the prior art for at least the following reason(s): The claimed invention is the obvious combination of two prior art techniques routinely utilized to treat cancer patients (i.e., administration of Dabrafenib as taught by US’378 and blood transfusions as taught by Cata as evidenced by Vaiyapuri), wherein the combination of the two prior art methods would predictably result in the treatment of the cancer patient, because the two techniques would be expected to merely perform the same functions in combination as they do separately (see, e.g., MPEP §§ 2143(I)(A), (C), (D).
No evidence of unexpected results commensurate in scope with the requirements of MPEP §§ 716, 716.01, and 716.02 have been placed on record to date.
Furthermore, there would be a reasonable expectation of success because the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)). Furthermore, it is well-within the ordinary skill in the art to make and use known compounds in known methods to obtain the results taught and suggested by the prior art.
Accordingly, claims 1-6 and 13 are rejected.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-3 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of copending Application No. 18/290665 (reference application; corresponding to US 20240325489 A1). Although the claims at issue are not identical, they are not patentably distinct from each other as explained below.
The copending claim sets overlap in scope. Regarding instant claims 1-3, both claim sets are directed to methods of treating the same types of cancers, including breast cancer, melanoma, lung cancer, and colon cancer (compare instant claim 3 with App’665 at claims 1 and 6), by administering to patients a therapeutic amount of Connexin 43 (compare instant claims 1-3 with App’665 at claims 1, 6, 10, 12), wherein the Cx43 may be delivered the same way (compare instant claim 14 with App’665 at 15-18, referring to expression vectors and nanoparticles).
Accordingly, the claims are directed to materially overlapping subject matter and are not patentably indistinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-6 and 13-14 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of copending Application No. 18/290665 (reference application; corresponding to US 20240325489 A1) in view of US2013/0172378 (Jul. 4, 2013).
The copending claim sets overlap in scope. Regarding instant claims 1-3, both claim sets are directed to methods of treating the same types of cancers, including breast cancer, melanoma, lung cancer, and colon cancer (compare instant claim 3 with App’665 at claims 1 and 6), by administering to patients a therapeutic amount of Connexin 43 (compare instant claims 1-3 with App’665 at claims 1, 6, 10, 12), wherein the Cx43 may be delivered the same way (compare instant claim 14 with App’665 at 15-18, referring to expression vectors and nanoparticles).
The claims differ as follows: The copending claims do not explicitly recite nor require treatment using the compound of dabrafenib.
However, regarding instant claims 1-6, 13-14, and the treatment of cancers by administering Dabrafenib, US’378 teaches, discloses, and claims methods of treating cancers in humans by administering a “therapeutically effective amount” of
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(see, e.g., US’378 at claims 5-7, noting that Formula (II), shown above, is Dabrafenib), wherein the cancer may be at least melanoma, breast cancer, lung cancer, or colon cancer (see, e.g., US’378 at claims 6-7, ¶[0033] noting that Dabrafenib is also referred to as “Compound B”), and wherein the “therapeutically effective amount” is understood to be from about 10 mg to 600 mg (see, e.g., US’378 at claims 6-7, ¶¶[0033], [0100], noting that Dabrafenib is also referred to as “Compound B”).
Obviousness analysis: Under an obviousness analysis (see, e.g., MPEP § 804(II)(B)(3)), it is noted that the scope and content of the patent claim relative to the application claims at issue have been discussed above (see, e.g., MPEP § 804(II)(B)(3)(A)), and that the differences are that the instant claims attempt to claim a different, but materially overlapping scope of methods, which differ by the lack of recitation of dabrafenib. However, as established by US’378 dabrafenib was an art-recognized compound disclosed for use in methods of treating cancers as presently claimed. Accordingly, the modification of the copending claims to include Dabrafenib would render the claims overlapping in scope, and the addition of Dabrafenib to methods of treating cancer would be obvious per MPEP §§ 2143(I)(C), (D), (G), as well as MPEP § 2144.06(I). Accordingly, c ombining known methods of treating the same types of cancer by simply combining two known compounds into a single treatment is obvious, because the compounds merely perform their art-recognized functions to yield predictable results, namely the treatment of cancer as expected (see, e.g., MPEP § 804(II)(B)(3)(B)).
This is a provisional nonstatutory double patenting rejection.
Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
US 7094201 discloses and claims methods of delivering polynucleotides encoding Cx43 to cardiac tissues in vivo (see, e.g., US’201 at claims, SEQ ID NO: 4).
US2006/0100668 A1 pertains to a device used to change the level of Connexin 43 in patients having melanoma, carcinomas, or breast cancers (see, e.g., US’668 at ¶¶[0310]-[0314]).
Huang et al.29 discloses that Cx43 expression suppresses transformation and tumorigenicity in human glioblastoma cells, and can thereby enhance chemotherapy-induced apoptosis (see, e.g., Huang at title, abs).
Hattori et al.30, teaches that non-viral delivery of Cx43 can inhibit in vivo tumor growth (see, e.g., Hattori at title, abs, Fig. 5 on 1435, Fig. 6 on 1436).
Bikou et al.31 pertains to the treatment of atrial arrhythmias in vivo using Connexin 43 gene therapy (see, e.g., Bikou at title, abs).
Rossello et al.32 discloses a viral vector encoding Cx43 (see, e.g., Rossello at 13223 at col II at §§ Viral Vector Production), which was utilized in vivo (see, e.g., Rossello at 13224 at col II at §§ In vivo Transplantation), wherein the inventors conclude that “Our findings suggest that increasing GJIC via overexpression of Cx43 can be a powerful tool to overcome limitations inherent in cell-cell communication and regeneration of tissue in 3D” and that the usage of Cx43 could potentially be extended “to other tissues by using Cx43 with other growth factors or stimuli that enhance the regeneration of a tissue of interest” (see, e.g., id. at 13223 at col I-II at bridging ¶, 13223 at col II at 1st full ¶).
Lu et al.33, discloses the usage of stem cells and a mito-Cx43 gene (see, e.g., Lu at title, abs).
Navi et al.34 discusses the relationship of arterial thromboembolism in patients with cancer (see, e.g., id. at title, abs).
Yeh et al.35, discusses the relationship of heart diseases and conditions, and cancer (see, e.g., id. at title, abs).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RANDALL L BEANE whose telephone number is (571)270-3457. The examiner can normally be reached Mon.-Fri., 7 AM to 2 PM ET.
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/RANDALL L BEANE/ Primary Examiner, Art Unit 1654
1 Examiner notes that Group I is directed to a claimed invention that was not previously claimed in the originally filed disclosure, and was first submitted in an Amendment filed 11/21/2023.
2 “Cx43” appears to be a subgenus of different sequences in the prior art per a cursory search on NCBI for “Connexin 43”, which pulls up 400+ different hits. If the claims are meant to be limited to a specific sequence of “Cx43”, then it should be clearly identified to the extent supported by the originally filed disclosure in the subsequent response to the instant requirement.
3 Dhillon et al., MAP kinase signalling pathways in cancer. Oncogene. 2007 May 14;26(22):3279-90. doi: 10.1038/sj.onc.1210421. PMID: 17496922; hereafter “Dhillon”.
4 Bonacquisti et al., Connexin 43 (Cx43) in cancer: Implications for therapeutic approaches via gap junctions. Cancer Lett. 2019 Feb 1;442:439-444. doi: 10.1016/j.canlet.2018.10.043. Epub 2018 Nov 22. PMID: 30472182; cited in Requirement mailed 10/29/2025’ hereafter “Bonacquist”.
5 Bonacquisti et al., Connexin 43 (Cx43) in cancer: Implications for therapeutic approaches via gap junctions. Cancer Lett. 2019 Feb 1;442:439-444. doi: 10.1016/j.canlet.2018.10.043. Epub 2018 Nov 22. PMID: 30472182; cited in Requirement mailed 10/29/2025’ hereafter “Bonacquist”.
6 GenBank: AAD37802.2, Connexin 43 [Homo sapiens], PRI 19-Dec-2000, 2 pages attached as pdf, also available at https://www.ncbi.nlm.nih.gov/protein/AAD37802.2 (last visited 3/16/2026)
7 Roell et al., Overexpression of Cx43 in cells of the myocardial scar: Correction of post-infarct arrhythmias through heterotypic cell-cell coupling. Sci Rep. 2018 May 8;8(1):7145. doi: 10.1038/s41598-018-25147-8. PMID: 29739982; PMCID: PMC5940892.
8 Fernandes et al., Cardiac cell therapy: overexpression of connexin43 in skeletal myoblasts and prevention of ventricular arrhythmias. J Cell Mol Med. 2009 Sep;13(9B):3703-12. doi: 10.1111/j.1582-4934.2009.00740.x. Epub 2009 Mar 6. PMID: 19438811; PMCID: PMC3189515; hereafter “Fernandes”.
9 Bonacquisti et al., Connexin 43 (Cx43) in cancer: Implications for therapeutic approaches via gap junctions. Cancer Lett. 2019 Feb 1;442:439-444. doi: 10.1016/j.canlet.2018.10.043. Epub 2018 Nov 22. PMID: 30472182; cited in Requirement mailed 10/29/2025’ hereafter “Bonacquist”.
10 Ableser et al., Connexin43 reduces melanoma growth within a keratinocyte microenvironment and during tumorigenesis in vivo. J Biol Chem. 2014 Jan 17;289(3):1592-603. doi: 10.1074/jbc.M113.507228. Epub 2013 Dec 2. PMID: 24297173; PMCID: PMC3894339; hereafter “Ableser”.
11 Dhillon et al., MAP kinase signalling pathways in cancer. Oncogene. 2007 May 14;26(22):3279-90. doi: 10.1038/sj.onc.1210421. PMID: 17496922; hereafter “Dhillon”.
12 Hattori et al., Non-viral delivery of the connexin 43 gene with histone deacetylase inhibitor to human nasopharyngeal tumor cells enhances gene expression and inhibits in vivo tumor growth. Int J Oncol. 2007 Jun;30(6):1427-39. PMID: 17487363; hereafter “Hattori”.
13 Hattori et al., Non-viral delivery of the connexin 43 gene with histone deacetylase inhibitor to human nasopharyngeal tumor cells enhances gene expression and inhibits in vivo tumor growth. Int J Oncol. 2007 Jun;30(6):1427-39. PMID: 17487363; hereafter “Hattori”.
14 Ableser et al., Connexin43 reduces melanoma growth within a keratinocyte microenvironment and during tumorigenesis in vivo. J Biol Chem. 2014 Jan 17;289(3):1592-603. doi: 10.1074/jbc.M113.507228. Epub 2013 Dec 2. PMID: 24297173; PMCID: PMC3894339; hereafter “Ableser”.
15 Dhillon et al., MAP kinase signalling pathways in cancer. Oncogene. 2007 May 14;26(22):3279-90. doi: 10.1038/sj.onc.1210421. PMID: 17496922; hereafter “Dhillon”.
16 Hattori et al., Non-viral delivery of the connexin 43 gene with histone deacetylase inhibitor to human nasopharyngeal tumor cells enhances gene expression and inhibits in vivo tumor growth. Int J Oncol. 2007 Jun;30(6):1427-39. PMID: 17487363; hereafter “Hattori”.
17 Roell et al., Overexpression of Cx43 in cells of the myocardial scar: Correction of post-infarct arrhythmias through heterotypic cell-cell coupling. Sci Rep. 2018 May 8;8(1):7145. doi: 10.1038/s41598-018-25147-8. PMID: 29739982; PMCID: PMC5940892.
18 Fernandes et al., Cardiac cell therapy: overexpression of connexin43 in skeletal myoblasts and prevention of ventricular arrhythmias. J Cell Mol Med. 2009 Sep;13(9B):3703-12. doi: 10.1111/j.1582-4934.2009.00740.x. Epub 2009 Mar 6. PMID: 19438811; PMCID: PMC3189515; hereafter “Fernandes”.
19 Ableser et al., Connexin43 reduces melanoma growth within a keratinocyte microenvironment and during tumorigenesis in vivo. J Biol Chem. 2014 Jan 17;289(3):1592-603. doi: 10.1074/jbc.M113.507228. Epub 2013 Dec 2. PMID: 24297173; PMCID: PMC3894339; hereafter “Ableser”.
20 Hattori et al., Non-viral delivery of the connexin 43 gene with histone deacetylase inhibitor to human nasopharyngeal tumor cells enhances gene expression and inhibits in vivo tumor growth. Int J Oncol. 2007 Jun;30(6):1427-39. PMID: 17487363; hereafter “Hattori”.
21 Ableser et al., Connexin43 reduces melanoma growth within a keratinocyte microenvironment and during tumorigenesis in vivo. J Biol Chem. 2014 Jan 17;289(3):1592-603. doi: 10.1074/jbc.M113.507228. Epub 2013 Dec 2. PMID: 24297173; PMCID: PMC3894339; hereafter “Ableser”.
22 Ableser et al., Connexin43 reduces melanoma growth within a keratinocyte microenvironment and during tumorigenesis in vivo. J Biol Chem. 2014 Jan 17;289(3):1592-603. doi: 10.1074/jbc.M113.507228. Epub 2013 Dec 2. PMID: 24297173; PMCID: PMC3894339; hereafter “Ableser”.
23 Cata et al., Perioperative blood transfusions and survival in patients with non-small cell lung cancer: a retrospective study. BMC Anesthesiol. 2013 Nov 15;13(1):42. doi: 10.1186/1471-2253-13-42. PMID: 24228905; PMCID: PMC3832885; cited in Requirement mailed 10/29/2025; hereafter “Cata”.
24 Vaiyapuri et al., Gap junctions and connexin hemichannels underpin hemostasis and thrombosis. Circulation. 2012 May 22;125(20):2479-91. doi: 10.1161/CIRCULATIONAHA.112.101246. Epub 2012 Apr 23. PMID: 22528526; PMCID: PMC3378664; cited in Requirement mailed 10/29/2025; hereafter “Vaivapuri”.
25 Ableser et al., Connexin43 reduces melanoma growth within a keratinocyte microenvironment and during tumorigenesis in vivo. J Biol Chem. 2014 Jan 17;289(3):1592-603. doi: 10.1074/jbc.M113.507228. Epub 2013 Dec 2. PMID: 24297173; PMCID: PMC3894339; hereafter “Ableser”.
26 Bonacquisti et al., Connexin 43 (Cx43) in cancer: Implications for therapeutic approaches via gap junctions. Cancer Lett. 2019 Feb 1;442:439-444. doi: 10.1016/j.canlet.2018.10.043. Epub 2018 Nov 22. PMID: 30472182; cited in Requirement mailed 10/29/2025’ hereafter “Bonacquist”.
27 Cata et al., Perioperative blood transfusions and survival in patients with non-small cell lung cancer: a retrospective study. BMC Anesthesiol. 2013 Nov 15;13(1):42. doi: 10.1186/1471-2253-13-42. PMID: 24228905; PMCID: PMC3832885; cited in Requirement mailed 10/29/2025; hereafter “Cata”.
28 Vaiyapuri et al., Gap junctions and connexin hemichannels underpin hemostasis and thrombosis. Circulation. 2012 May 22;125(20):2479-91. doi: 10.1161/CIRCULATIONAHA.112.101246. Epub 2012 Apr 23. PMID: 22528526; PMCID: PMC3378664; cited in Requirement mailed 10/29/2025; hereafter “Vaivapuri”.
29 Huang et al., Connexin 43 (cx43) enhances chemotherapy-induced apoptosis in human glioblastoma cells. Int J Cancer. 2001 Apr 1;92(1):130-8. PMID: 11279616; hereafter “Huang”.
30 Hattori et al., Non-viral delivery of the connexin 43 gene with histone deacetylase inhibitor to human nasopharyngeal tumor cells enhances gene expression and inhibits in vivo tumor growth. Int J Oncol. 2007 Jun;30(6):1427-39. PMID: 17487363; hereafter “Hattori”.
31 Bikou et al., Connexin 43 gene therapy prevents persistent atrial fibrillation in a porcine model. Cardiovasc Res. 2011 Nov 1;92(2):218-25. doi: 10.1093/cvr/cvr209. Epub 2011 Jul 28. PMID: 21799069.
32 Rossello et al., Connexin 43 as a signaling platform for increasing the volume and spatial distribution of regenerated tissue. Proc Natl Acad Sci U S A. 2009 Aug 11;106(32):13219-24. doi: 10.1073/pnas.0902622106. Epub 2009 Jul 23. PMID: 19628695; PMCID: PMC2726403.
33 Lu et al., Subcellular preconditioning of stem cells: mito-Cx43 gene targeting is cytoprotective via shift of mitochondrial Bak and Bcl-xL balance. Regen Med. 2012 May;7(3):323-34. doi: 10.2217/rme.12.13. PMID: 22594326; PMCID: PMC3380626.
34 Navi et al., Risk of Arterial Thromboembolism in Patients With Cancer. J Am Coll Cardiol. 2017 Aug 22;70(8):926-938. doi: 10.1016/j.jacc.2017.06.047. PMID: 28818202; PMCID: PMC5667567.
35 Yeh et al., Cancer and Clot: Between a Rock and a Hard Place, Journal of the American College of Cardiology, Volume 70, Issue 8, 2017, Pages 939-941, ISSN 0735-1097, https://doi.org/10.1016/j.jacc.2017.07.719.
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