DETAILED ACTION
Claims 1-3, 6-7, 9-11, 40, and 42 are pending in the instant application and being examined on the merit.
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 .
Information Disclosure Statement
The information disclosure statements filed 5/25/2023 (both information disclosure statements were filed at this date) fail to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. It has been placed in the application file, but the information referred to therein has not been considered.
Drawings
The drawings are objected to because:
Instant Figure 11 contains amino acid sequences which are not followed by a sequence identifier.
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.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - Sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.831(c). Sequence identifiers for sequences (i.e., “SEQ ID NO:X” or the like) must appear either in the drawings or in the Brief Description of the Drawings. The examiner has noted that Figure 11 contains amino acid sequences which are not followed by sequence identifiers.
Required response – Applicant must provide:
Amended drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers (i.e., “SEQ ID NO:X” or the like) into the Brief Description of the Drawings, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Specification
The disclosure is objected to because of the following informalities:
“SEQ ID NOS” should read “SEQ ID NOs” (page 4, paragraphs [0015], [0016])
Appropriate correction is required.
Claim Objections
Claim 40 is objected to because of the following informalities:
“TGFP” should read “TGFβ”.
Appropriate correction is required.
Claim Interpretation
The instant specification defines agents that modulate the expression or activity of a MAP kinase pathway as an inhibitor or antagonist of a MAP kinase pathway or MAP kinase component that selectively blocks MAP kinase signaling (page 33, paragraph [0117]). Thus, agents that modulate the activity of MAP kinase pathway signaling are interpreted as agents that block MAP kinase signaling.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-3, 6-7, 9-11, 40, and 42 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating a subject having Marfan Syndrome or a Marfan-associated condition comprising administering to the subject an effective amount of an agent that modulates the activity of p38MAPK alpha (MAPK14), ERK1/2, or JNK1, does not reasonably provide enablement for a method of treating a subject having (1) treating a subject at risk of developing Marfan Syndrome or a Marfan-associated condition or (2) having Marfan Syndrome or a Marfan-associated condition comprising administering to the subject an effective amount of an agent that modulates the activity of any of member of the vast MAPK family signaling pathways. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Claim 1 is for a method for treating a subject having or at risk of developing Marfan Syndrome or a Marfan-associated condition but the specification and the state of the art do not teach a method for treating a subject at risk of developing Marfan Syndrome or a Marfan-associated condition comprising administering to the subject an effective amount of an agent that modulates the activity of MAP kinase pathway signaling; thereby treating the subject. Claims 2-3, 6-7, 9-11, 40, and 42 are further dependent on claim 1 without requiring treatment.
Claims 1-3, 6-7, 9-11, 40, and 42 are for a method of treating Marfan Syndrome or a Marfan-associated condition comprising administering to the subject an agent that modulates the activity of the MAP kinase pathway signaling. However, the instant application did not identify which specific member(s) of the MAP kinase signaling pathway the agent modulates.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." These
factors include, but are not limited to:
The breadth of the claims;
The nature of the invention;
The state of the prior art;
The level of one of ordinary skill;
The level of predictability in the art;
The amount of direction provided by the inventor;
The existence of working examples; and
The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Scope of the claimed genus and nature of the invention.
Claims 1-3, 6-7, 9-11, 40, and 42 are for a method of treating a subject having or at risk of developing Marfan Syndrome or a Marfan-associated condition comprising administering to the subject an effective amount of an agent that modulates the activity of MAP kinase pathway signaling; thereby treating the subject.
Claims 1-3, 6-7, 9-11, 40, and 42 are for a method of treating Marfan Syndrome or a Marfan-associated condition comprising administering to the subject an effective amount of an agent that modulates the activity of MAP kinase pathway signaling.
State of the Relevant Art; level of one of ordinary skill; and level of predictability of the art.
Marfan syndrome ([OMIM] 154700; hereinafter MFS) is a systemic disorder caused by mutations in the extracellular matrix protein fibrillin-1 (Ramirez and Dietz, Current Opinion in Genetics & Development, 2007, 17(3):252-258; hereinafter Ramirez; page 252, left column, second paragraph). First described by Antoine-Bernard Marfan in an 1896 case report of a young girl with unusual musculoskeletal features, a 50-year-long analysis of the clinical and genetic features of Marfan syndrome ultimately led Victor McKusick to delineate it as the founding member of a larger group of congenital conditions that he defined as the heritable disorders of the connective tissue, and which he predicted to be the result of structural or metabolic dysfunctions of extracellular matrix proteins. The demonstration in 1991 that mutations in the fibrillin-1 gene (FBN1) cause Marfan syndrome confirmed McKusick's prediction, and, fifteen years later, the unexpected finding that increased transforming growth factor beta (TGFβ) signaling is part of the molecular pathogenesis of Fbn1-deficient mice has paved the way to a new drug-based strategy against the life-threatening manifestations of MFS (page 252, Introduction). Ramirez additionally teaches that the phenotype of MFS typically involves manifestations in the cardiovascular, skeletal and ocular systems (page 252, right column, second paragraph). The most striking and immediately evident manifestation in MFS patients often involves a disproportionate increase in linear bone growth that causes overt malformations of the digits, limbs and anterior chest wall. Cardiovascular manifestations include progressive aortic root enlargement and abnormally thick and elongated valve leaflets. Ascending aortic aneurysm can precipitate life-threatening complications such as aortic regurgitation, dissection or rupture (page 252, right column, second paragraph). Ramirez further teaches that the discovery that perturbed TGFβ signaling contributes to MFS pathogenesis predicted that conditions that display Marfan syndrome-like manifestations might be caused by mutations in different components of the TGFβ signaling network (regulators or transducers), e.g. Loeys-Dietz syndrome (OMIM 609192), Ehlers-Danlos syndrome (OMIM 130050), and Arterial tortuosity syndrome (OMIM 208050) (page 255-256, “Clinical spectrum of TGFβ signaling disorders of the connective tissue” Section).
As mouse models of MFS have revealed that mutations in the fibrillin-1 gene (Fbn1) also promote promiscuous activation of latent TGF-β with adverse consequences to cellular activities, Carta teaches that p38 MAPK is an early contributor during aneurysm progression in Fbn1-null mice (Carta et al, J Biol Chem, 2009, 284(9): 5630-5636, IDS entered on 5/25/2023; page 5630, Abstract; page 5631, left column, second paragraph). Carta discloses that the functional relationship between p38 MAPK and Smad2/3 was examined because of the central role that p38 MAPK plays in multiple stress response pathways and in TGF-β signaling as well (page 5635, left column, first paragraph). Carta further teaches loss of fibrillin-1 in Fbn1-null mouse aortas promotes TGF-β- and/or ECM-mediated stimulation of p38 MAPK, and this in turn augments Smad2/3 signaling and perhaps induces TGF-β activators. As a result, early activation of p38 MAPK and conceivably other MAPKs may also cooperate with Smad signaling in executing specific cellular programs that further contribute to aneurysm progression in MFS (page 5635, left column, second paragraph).
By the time of the filing of the instant application, it was well established in the art that effective surgical therapy for the most life-threatening manifestation, aortic root aneurysm, had led to a nearly normal lifespan for affected individuals who were appropriately recognized and treated. Traditional medical therapies, such as beta-adrenergic receptor blockade, were used to slow pathologic aortic growth and decrease the risk of aortic dissection by decreasing hemodynamic stress. Additionally, TGFβ antagonists have shown great success in improving or preventing several manifestations of MFS in mouse models, including aortic aneurysm (Judge and Dietz, Annual Review of Medicine, 2008, 59: 43-59; page 43, Abstract). Carta also discloses that the demonstration that p38 MAPK is implicated in constitutive activation of Smad2/3 signaling in the aortas of Fbn1-null mice points to another potential opportunity for therapy in MFS (Carta et al, J Biol Chem, 2009, 284(9): 5630-5636; page 5635, left column, second paragraph). However, while Judge teaches that there are prophylactic antibiotics available for preventing bacterial endocarditis in MFS patients (Judge and Dietz, Annual Review of Medicine, 2008, 59: 43-59; page 53, “Endocarditis Prophylaxis” Section), the prior art does not describe a treatment for prevention of Marfan Syndrome.
It is well known in the art that there are two distinct ways of intracellular pathways in Marfan Syndrome through which elevated TGFβ levels can exert its detrimental effects: the canonical pathway mediated by the Smad proteins and the non-canonical signaling pathway mediated by p38, ERK1/2, and JNK1 (Benke et al, Cardiology Journal, 2013, 20(3): 227-234; Figure 2; page 229, right column, last paragraph – page 231, right column, first paragraph). Holm also teaches that TGFβ induces MAPK cascades, which includes ERK1/2, JNK1, and p38 (Holm et al, Science, 2011, 332(6027):358-361; IDS entered on 5/25/2023; page 358, second column, first paragraph; Fig. 1), which defines 1) a critical role for noncanonical TGFβ-dependent signaling in aneurysm pathogenesis in MFS; and 2) inhibition of ERK1/2 or JNK1 activation as possible therapeutic strategies for MFS (page 361, second column, second paragraph). Holm teaches that inhibition of ERK1/2 activation via treatment with RDEA119, wherein RDEA119 is an inhibitor specific for ERK1/2 whereas JNK1 and p38 activation remained unchanged, in Fbn1C1039G/+ mice (a validated mouse model for MFS) significantly decreased aortic root growth compared to placebo-treated Fbn1C1039G/+ littermates (page 359, first column, first and second paragraphs). Holm further teaches that inhibition of JNK1 activation via treatment with SP600125, wherein SP600125 is a JNK inhibitor, in both S4+/-:Fbn1C1039G/+ mice (MFS mice with Smad4 deletion) and Fbn1C1039G/+ mice ameliorated the disease (page 360, third column, fourth paragraph – page 361, first column, second paragraph; Fig. 4).
Xiong teaches that doxycycline, a nonspecific matrix metalloproteinase (MMP) inhibitor, decreases ERK1/2 signaling, which is one of the critical noncanonical downstream pathways of TGFβ in MFS that leads to aneurysm formation, exhibiting similar protective effects on the matrix as losartan, an angiotensin II receptor blocker, thus delaying aneurysm formation and rupture (Xiong et al, Circulation Research, 2012, 110(12): e92-e101, IDS entered on 5/25/2023; page e93, left column, third paragraph).
Carta teaches that in Fbn1-null primary VSMC cultures transfected with small interfering RNA specific for p38α MAPK (MAPK14) reduced phospho-Smad2 levels by approximately 30%, demonstrating that p38 α MAPK is implicated in constitutive activation of Smad 2/3 signaling, pointing to another potential opportunity for therapy of MFS (Carta et al, J Biol Chem, 2009, 284(9): 5630-5636, IDS entered on 5/25/2023; page 5631, left column, third and fourth paragraphs; page 5633, right column, first paragraph; Figure 3; page 5635, left column, last paragraph).
Finally, Doyle teaches that a number of potential candidate genes were identified within the regions of interest, including Mmp17, which encodes an indirect activator of latent TGFβ and is involved in extracellular matrix homeostasis and Map2k6, which encodes a protein that is activated by Map3k4, and itself can activate p38 (Doyle, “Elucidation of the Pathogenesis of TGF-Beta Vasculopathies Identifies Novel Therapeutic Strategies, Dissertation submitted to the Johns Hopkins University, October 2015, IDS entered on 5/25/2023; page 159, second paragraph; page 162, second paragraph; page 203, third paragraph-page 204, first paragraph). In wild type and Marfan mice that retain either one or two normal copies of MAP3k4, the direct upstream activator of Map2k6, Doyle teaches that there was a significant rescue of aortic root growth in Map3k4 haploinsufficient mice (page 163, Figure 5-24). Martin-Alonso teaches that Marfan Syndrome is a genetic syndrome that predisposes to Thoracic aortic aneurysms and acute aortic dissections (TAAD) and discloses that Mmp17 deficiency led to increased susceptibility to TAA (Martin-Alonso et al, Circulation Research, 2015, 117(2):e13-e26, IDS entered on 5/25/2023; page e15, third paragraph). Furthermore, Martin-Alonso teaches immunostaining analysis revealed that lack of Mmp17 resulted in reduced JNK activation, suggesting that Mmp17 is required for proper activation of JNK signaling (Figure 7; page e21, first paragraph - third paragraph).
Summary of Species disclosed in the original specification; the amount of direction provided by the inventor, existence of working examples; and quality of experimentation needed to make or use the invention based on the content of the disclosure.
The instant specification only identifies Marfan Syndrome treatment in instant Figure 2 of treating 129 MFS mice with either the ARB losartan or the inhibitor of Erk1/2 activation RDEA119 and Figure 3 for treatment with the EGFR inhibitor erlotinib in 129 MFS mice. The MFS mice already have Marfan Syndrome before treatment. There are no MFS prevention studies in the instant specification.
The instant specification teaches a kit for identifying a subject having or at risk of developing Marfan Syndrome or a Marfan-associated condition that includes primers specific for amplification of MMP17, MAP2K6 and/or MAP3K4; a probe oligonucleotide, optionally fluorescently labeled, that specifically detects the presence of a MMP17, MAP2K6 and/or MAP3K4 amplicon, wherein detection of elevated expression of MMP17, MAP2K6 and/or MAP3K4 identifies the subject as having or at risk of developing Marfan Syndrome or a Marfan-associated condition. Figure 4C discloses the mRNA expression of Map3K4 in MFS patients with normal, mild and severe aortic diseases, disclosing increased level of Map3k4 in MFS patients with mild or severe aortic disease.
The instant specification teaches a decrease in aortic root size in 6-month-old MFS mice lacking either one or two functional Mmp17 and Map2k6 alleles in Figure 3C. Figure 3D teaches knockout of both Mmp17 and Map2k6 led to attenuation of canonical and noncanonical signaling cascades, e.g. Erk1/2 and p38. Figure 4D discloses aortic root growth from 2-months of age in WT and MFS mice either retaining or haploinsufficient for Map3k4, wherein the aortic root growth from 2-6months was reduced in MFS mice haploinsufficient for Map3k4.
Conclusion
The Applicant does not have enablement for a method of treating a subject at risk of developing Marfan Syndrome or a Marfan-associated condition comprising administering to the subject an effective amount of an agent that modulates the activity of MAP kinase pathway signaling; thereby treating the subject in claims 1-3, 6-7, 9-11, 40, and 42.
The Applicant does not have enablement for a method of treating a subject having Marfan Syndrome or a Marfan-associated condition comprising administering to the subject an effective amount of an agent that modulates the activity of any of member of the vast MAPK family signaling pathways in claims 1-3, 6-7, 9-11, 40, and 42.
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.
(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, 2, 6, 9-11, and 40 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Dietz et al (US 2014/0148498 A1; hereinafter Dietz).
Regarding instant claim 1, Dietz teaches a method of treating a patient having Marfan syndrome or a Marfan-associated condition involving administering to the subject an effective amount of an agent that modulates the activity of noncanonical TGFβ signaling; thereby treating the patient (page 26, paragraph [0013]), wherein the noncanonical TGFβ signaling status is MEK, ERK1/2, or JNK1 activity (page 26, paragraph [0019] and [0020]).
Regarding instant claim 2, Dietz teaches that the agent that modulates the activity of the noncanonical TGFβ signaling pathway is an inhibitor of MEK, ERK1/2, or JNK (page 26, paragraph [0019]).
Regarding instant claim 6, Dietz teaches that the agent that modulates the activity of the noncanonical TGFβ signaling pathway is an inhibitor of MEK, ERK1/2, or JNK, wherein the agent is a small molecule, e.g. SP600125 (page 26, paragraph [0019]; page 39, paragraph [0093]-[0094]).
Regarding instant claims 9, 10, and 11, Dietz teaches that the Marfan syndrome-associated disease or disorder is a clinical condition associated with Marfan syndrome, wherein the disease or disorder is an aneurysm, an aortic aneurysm, or emphysema (page 26, paragraph [0019]).
Regarding instant claim 40, Dietz teaches the agent that modulates the activity of the noncanonical TGFβ signaling pathway, i.e. MAP kinase signaling pathway, is a TGFβ signaling pathway inhibitor (page 26, paragraph [0019]).
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.
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.
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.
Claims 3, 7, and 42 are rejected under 35 U.S.C. 103 as being unpatentable over Dietz et al (US 2014/0148498 A1; hereinafter Dietz), and further in view of Xiong et al (Circulation Research, 2012, 110(12):e92-e101, IDS entered on 5/25/2023; hereinafter Xiong), Wang et al (J Biol Chem, 1999, 274(46):33043-33049; hereinafter Wang) and Kumar et al (AJP, 2010, 177(1):248-260; hereinafter Kumar).
The teachings of Dietz are discussed above in the 102 rejection.
However, Dietz does not teach a method for treating a subject having Marfan Syndrome or a Marfan-associated condition comprising administering to the subject an effective amount of an agent that modulates the activity of MAP kinase pathway signaling wherein the agent that modulates the activity of MAP kinase pathway signaling comprises Batimastat, a small molecule and inhibitor of MMP17; thereby treating the patient.
The deficiency is resolved by Xiong, Wang and Kumar.
Xiong teaches that studies using mouse models of MFS have shown that activation of TGFβ and the concomitant upregulation of matrix metalloproteinases (MMPs) contribute to aneurysm, which is one of the main cardiovascular complications of MFS (page e92, Abstract ; page e92, right column, second paragraph-e93, left column, first paragraph). Xiong also teaches that doxycycline, a nonspecific MMP inhibitor, decreases Smad2 and Erk1/2 signaling, which is the critical noncanonical downstream pathway of TGF-β in MFS. Furthermore, doxycycline has been shown to exhibit similar protective effects on the matrix as losartan, delaying aneurysm formation and rupture, and when combined, these drugs have been shown to result in significant prolongation of survival (page e93, left column, third paragraph)
Wang teaches that small molecule inhibitors, such as Batimastat and Galardin (GM 6001) are effective MMP-17(MT4-MMP7) inhibitors (page 33049, left column, paragraph 3; page 33047, left column, first paragraph and Table II).
Kumar teaches that inhibition of MMPs using Batimastat reduced the activation of mitogen-activated protein kinases and activator protein-1 in myofibers of mdx mice (page 248, Abstract; page 257, Figure 7A; page 255, right column, first paragraph).
Regarding instant claims 3, 7, and 42, it would have been obvious for a person having ordinary skill in the art at the time of filing to take the method of treating a patient having Marfan syndrome or a Marfan-associated condition comprising administering to the subject an effective amount of an agent that modulates the activity of noncanonical TGFβ signaling, wherein the agent is an MMP inhibitor (taught by Xiong), thereby treating the patient, wherein the noncanonical TGFβ signaling status is MEK, ERK1/2, or JNK1 activity as taught by Dietz and include Batimastat, a small molecule inhibitor that inhibits MMP17 as taught by Wang, as the agent thereby reducing mitogen activated protein kinase pathway signaling as taught by Kumar. This is obvious because, Dietz teaches a method of treating a patient having Marfan syndrome or a Marfan-associated condition comprising administering to the subject an effective amount of an agent that modulates the activity of noncanonical TGFβ signaling, wherein the noncanonical TGFβ signaling status is MEK, ERK1/2, or JNK1 activity, Xiong teaches a nonspecific MMP inhibitor the delayed aneurysm, one of the main cardiovascular complications of MFS, by decreasing Erk1/2 signaling, which is a critical noncanonical downstream pathway of TGF-β in MFS, Wang teaches that the small molecule inhibitor, Batimastat, is an effective MMP-17 inhibitor, and Kumar teaches that inhibition of MMPs using Batimastat reduced the activation of mitogen-activated protein kinases. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to take the method of treating a patient having Marfan syndrome or a Marfan-associated condition comprising administering to the subject an effective amount of an agent (e.g. MMP inhibitor taught by Xiong) that modulates the activity of noncanonical TGFβ signaling, wherein the noncanonical TGFβ signaling status is MEK, ERK1/2, or JNK1 activity as taught by Dietz and include the agent wherein the agent is Batimastat (instant claim 7), a small molecule inhibitor that inhibits MMP17 (instant claims 3 and 42) as taught by Wang, thereby reducing mitogen activated protein kinase pathway signaling as taught by Kumar to form the instant method for treating a subject having Marfan Syndrome or a Marfan-associated condition comprising administering to the subject an effective amount of an agent, wherein the instant agent is a small molecule inhibitor Batimastat that modulates the activity of MAP kinase pathway signaling by inhibiting MMP17; thereby treating the subject.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jieun Ham whose telephone number is (571)272-7779. The examiner can normally be reached Monday - Thursday 7-3.
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/J.H./Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643