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 .
Election/Restrictions
Applicant’s election of the species SEQ ID NO: 3 in the response filed May 5, 2026, is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)). Prior art was found on the elected species as well as on SEQ ID NOs: 2, 4-6 and 8-11.
Claim 3 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. The elected peptide SEQ ID NO: 3 is not an antibody and therefore does not read on claim 3.
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 1-2 and 4-16 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 protecting against aortic rupture in patients with Marfan Syndrome using TREM-1 inhibitors comprising SEQ ID NOs: 2-11, does not reasonably provide enablement for the full scope of the claims. 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.
To comply with the enablement requirements of 35 U.S.C. §112, first paragraph, a specification must adequately teach how to make and how to use a claimed invention throughout its scope, without undue experimentation. Plant Genetic Systems N.V. v. DeKalb Genetics Corp., 315 F.3d 1335, 1339, 65 USPQ2d 1452, 1455 (Fed. Cir. 2003). There are a variety of factors which may be considered in determining whether a disclosure would require undue experimentation. These factors include: (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
The Nature of the Invention
The invention is in the technical field of treating Marfan Syndrome using inhibitors of Triggering receptor expressed on myeloid cells 1 (TREM-1).
The breadth of the claims
BRI of the claim term “treating” includes prophylactic, preventative, curative, and disease modifying treatments (see the definition of “treat” on page 4 of the specification). Therefore, BRI of the patient population a patient in need of treatment of Marfan Syndrome includes patients at risk of contracting Marfan Syndrome, patients diagnosed with Marfan Syndrome, patients suffering from Marfan Syndrome, and patients at risk of a relapse of Marfan Syndrome. Marfan Syndrome is a systemic disease of connective tissue caused by mutations of the FBN1 gene (15q21), which codes for fibrilline-1, an essential connective tissue protein. The condition has cardiovascular, musculoskeletal, ophthalmic, and pulmonary symptoms and effects (see the definition of “Marfan Syndrome” on page 3 of the specification). Disease modifying treatments may modulate any cardiovascular, musculoskeletal, ophthalmic, and/or pulmonary symptom and/or effect. This scope is applicable to claims 1-2 and 4-15.
BRI of the claim term “TREM-1 inhibitor” is any compound, chemical, antibody, or peptide that directly or indirectly decreases the activity and/or expression of TREM-1 (see the definition on page 6 of the specification). This broad scope is applicable to claims 1-2.
Claims 4-15 are limited to peptides as follows:
Claim 4 is limited to peptides of any length and amino acid sequence that is able to directly or indirectly decreases the activity and/or expression of TREM-1.
Claim 5 is limited to SEQ ID NOs: 2-11.
Claims 6-10 and 15 are limited to fragments of human TLT-1, or sequences having at least 60% identity thereto, or function-conservative variants or derivatives thereof that are able to directly or indirectly decreases the activity and/or expression of TREM-1. Claims 6 and 15 are the broadest and can be based on any fragment of human TLT-1, whereas claims 7-10 are based on SEQ ID NOs: 2-6.
Claims 11-14 and 16 are limited to fragments of human TREM-1, or sequences having at least 60% identity thereto, or function-conservative variants or derivatives thereof that are able to directly or indirectly decreases the activity and/or expression of TREM-1. Claims 11 and 16 are the broadest and can be based on any fragment of human TREM-1, whereas claims 12-14 are based on SEQ ID NOs: 7-11.
The State of the Prior Art
The Examiner is not aware of prior art disclosing the use of TREM-1 inhibitors to treat, prevent, cure, or modify the disease in patients with Marfan Syndrome. The specification states that the only treatment used for Marfan Syndrome is a beta-blocker, propranolol, which limits aortic dilatation and the risk of dissection (p. 1). The specification also teaches that other than surgery, treatment options are limited (p. 2).
Gibot et al. (WO 2014/037565) teach peptides derived from Triggering receptor expressed on myeloid cells 1 (TREM-1) and TREM-like transcript 1 (TLT-1). The prior art peptides SEQ ID NOs: 3-7 and 9-12 (p. 7, Table 1) are identical to the instantly claimed TREM-1 inhibitor peptides SEQ ID NOs: 2-6 and 8-11, respectively. Gibot et al. teach that TREM-1- and TLT-1-derived peptides function as TREM-1 inhibitors and can be used in methods of treating cardiovascular diseases, including aneurysm (p. 14, lines 20 - p. 16, line 11). Gibot et al. teach pharmaceutical compositions comprising a therapeutically effective amount of the TREM-1 inhibitor peptides (p. 17, lines 5-27). Although Gibot et al. teach that TREM-1 inhibitor peptides can be used in methods of treating cardiovascular diseases in general, including aneurysm (p. 14, lines 20 - p. 16, line 11), Gibot et al. do not teach a method of treating Marfan Syndrome patients, including those suffering from or at risk of developing abdominal aortic aneurysm.
Hagerty et al. teach that patients with Marfan Syndrome are at risk for developing abdominal aortic aneurysm (abstract). Although Hagerty et al. describe the risk of abdominal aortic aneurysm in Marfan Syndrome, they do not teach a treatment method at all let alone with TREM-1 inhibitors.
Vandestienne et al. explore the role of TREM-1 in abdominal aortic aneurysm (AAA) using a mouse model of angiotensin II-induced (AngII-induced) AAA (p. 2, col. 1, para. 2). Vandestienne et al. teach that TREM-1 expression was detected in mouse aortic aneurysm and colocalized with macrophages (p. 2, col. 1-2, bridging para; Figure 1). Vandestienne et al. teach that Trem1 gene deletion (Apoe-/-Trem1-/-) limited both AAA development and severity (p. 2, col. 1-2, bridging para; Figure 1). Vandestienne et al. teach that TREM-1 pharmacological blockade with LR-12 peptide, which is identical to instant SEQ ID NO: 3, also limited both AAA development and severity (pp. 2-3, bridging para.; Figure 2). Vandestienne et al. teach that in human AAA, TREM-1 was detected and TREM1 mRNA expression correlated with SELL mRNA expression, and that circulating levels of sTREM-1 were increased in patients with AAA when compared with patients without AAA (pp. 6-9, bridging paras.; Figure 6). Vandestienne et al. conclude that TREM-1 is involved in AAA pathophysiology and may represent a promising therapeutic target in humans (pp. 10-11, bridging para.). Although Vandestienne et al. describe the use of TREM-1inhibitors to treat abdominal aortic aneurysm, they nowhere disclose treatment of this condition in Marfan Syndrome patients.
The Predictability or Unpredictability of the Art
The prior art pertaining to peptide structure and function is highly unpredictable. The peptide art is replete with examples of amino acid changes that have no effect on function as well as with examples of single changes that have major effect on function. In general, empirical evidence is required to determine a structure-function relationship for a peptide. In the instant case, Gibot et al. (WO 2014/037565) teach TREM-1 inhibitor peptides SEQ ID NOs: 3-7 and 9-12 (p. 7, Table 1) but do not characterize any variants, derivatives, or fragments thereof. Therefore, the level of unpredictability with respect to the structure of TREM-1 peptide inhibitors is high.
The prior art pertaining to the development of pharmaceuticals is highly unpredictable. The prior art is replete with examples of candidate drugs that ultimately fail to have clinical efficacy. In the instant case, the prior art does not recognize TREM-1 as a target for Marfan Syndrome. Furthermore, the prior art does not recognize any means to prevent or cure Marfan Syndrome, or to treat all symptoms or effects of Marfan Syndrome on the cardiovascular, musculoskeletal, ophthalmic, and/or pulmonary systems of the patient.
The Level of Guidance in the Specification
The level of guidance in the specification is insufficient to determine which of the countless species encompassed by the claim can be used in the claimed method. For claims 1-2, the specification does not describe a non-peptide molecule that can be used to treat Marfan Syndrome. For claims 4-16, the data do not suggest the physical basis for the TREM-1 inhibitory peptide activity and therefore do not describe which substitutions, deletions or additions could be made while preserving function of the disclosed peptides. The specification does not describe how the peptides operate to inhibit TREM-1 and treat Marfan Syndrome nor does it describe which residues are important for this function. Understanding the physical basis for TREM-1 inhibition and Marfan Syndrome treatment and the correlation between structure and function is critical to determining which of the countless sequences that meet the structural requirements of the genus also meet the functional requirements of the genus.
The Presence or Absence of Working Examples
The specification demonstrates that TREM-1 is expressed by macrophages in the aortic wall of Marfan (Figure 1), that TREM-1 deficiency protects against aortic rupture in a mouse model of Marfan Syndrome (Figures 2-3), and that overstimulation of TREM-1 aggravates aorta rupture in Marfan mice (Figure 4) (pp. 13-14). Specifically, the specification presents the study of crossing fibrillin-1 hypomorphic mgR/mgR mice (a mouse model of Marfan Syndrome) with Trem-1 deficient mice. These mgR/mgR/Trem-1-/- mice showed significantly reduced aortic rupture and improved survival suggesting that deficiency of TREM-1 can prevent aortic rupture in Marfan Syndrome (p. 14). However, the specification does not reduce to practice treatment of Marfan Syndrome with a single TREM-1 inhibitor, including a peptide.
The Quantity of Experimentation Necessary
Considering the factors above, the skilled artisan would be burdened with undue experimentation in determining if one of the claimed TREM-1 inhibitors would be effective at treating, preventing, curing, or modulating any aspect of Marfan Syndrome other than the aortic rupture using SEQ ID NOs: 2-11. The skilled artisan would be burdened with testing a broad range of compounds, antibodies, and peptides in assays for TREM-1 inhibition. The active inhibitors would then have to be subjected to animal models of Marfan Syndrome. The experimentation required represents years of inventive effort. When the above factors are weighed, it is the examiner's position that one skilled in the art could not practice the invention without undue experimentation.
Therefore, in view of the Wands factors, the claims appear to require undue experimentation to use the full scope of the claimed invention.
Claims 1-2, 4, and 6-16 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.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.
BRI of the claim term “treating” includes prophylactic, preventative, curative, and disease modifying treatments (see the definition of “treat” on page 4 of the specification). Therefore, BRI of the patient population a patient in need of treatment of Marfan Syndrome includes patients at risk of contracting Marfan Syndrome, patients diagnosed with Marfan Syndrome, patients suffering from Marfan Syndrome, and patients at risk of a relapse of Marfan Syndrome. Marfan Syndrome is a systemic disease of connective tissue caused by mutations of the FBN1 gene (15q21), which codes for fibrilline-1, an essential connective tissue protein. The condition has cardiovascular, musculoskeletal, ophthalmic, and pulmonary symptoms and effects (see the definition of “Marfan Syndrome” on page 3 of the specification). Disease modifying treatments may modulate any cardiovascular, musculoskeletal, ophthalmic, and/or pulmonary symptom and/or effect. This scope is applicable to claims 1-2 and 4-15.
BRI of the claim term “TREM-1 inhibitor” is any compound, chemical, antibody, or peptide that directly or indirectly decreases the activity and/or expression of TREM-1 (see the definition on page 6 of the specification). This broad scope is applicable to claims 1-2.
Claims 4-15 are limited to peptides as follows:
Claim 4 is limited to peptides of any length and amino acid sequence that is able to directly or indirectly decreases the activity and/or expression of TREM-1.
Claim 5 is limited to SEQ ID NOs: 2-11.
Claims 6-10 and 15 are limited to fragments of human TLT-1, or sequences having at least 60% identity thereto, or function-conservative variants or derivatives thereof that are able to directly or indirectly decreases the activity and/or expression of TREM-1. Claims 6 and 15 are the broadest and can be based on any fragment of human TLT-1, whereas claims 7-10 are based on SEQ ID NOs: 2-6.
Claims 11-14 and 16 are limited to fragments of human TREM-1, or sequences having at least 60% identity thereto, or function-conservative variants or derivatives thereof that are able to directly or indirectly decreases the activity and/or expression of TREM-1. Claims 11 and 16 are the broadest and can be based on any fragment of human TREM-1, whereas claims 12-14 are based on SEQ ID NOs: 7-11.
Only those structures meeting the structural and functional requirements of the TREM-1 inhibitor genus are encompassed by the claims. Although with the aid of a computer it may be possible to determine the amino acid sequences of the peptides that meet the structural requirements of the claims, it is not readily apparent from the claims or the specification which of these sequences are also able to directly or indirectly decreases the activity and/or expression of TREM-1 and treat Marfan Syndrome.
The prior art pertaining to peptide structure and function is highly unpredictable. The peptide art is replete with examples of amino acid changes that have no effect on function as well as with examples of single changes that have major effect on function. In general, empirical evidence is required to determine a structure-function relationship for a peptide. In the instant case, Gibot et al. (WO 2014/037565) teach TREM-1 inhibitor peptides SEQ ID NOs: 3-7 and 9-12 (p. 7, Table 1) but do not characterize any variants, derivatives, or fragments thereof. Therefore, the level of unpredictability with respect to the structure of TREM-1 peptide inhibitors is high.
No embodiments of the invention were reduced to practice: the specification does not reduce to practice treatment of Marfan Syndrome with a single TREM-1 inhibitor. Therefore, the instant specification has failed to meet the written description requirement by actual reduction to practice of a representative number of species alone.
The specification discloses the full structure of several TREM-1 inhibitors: SEQ ID NOs: 2-11.
The specification does not disclose a partial structure of a peptide that meets the structural requirements of the genus. Although one of ordinary skill in the art could determine if a given amino acid sequence meets the structural requirements of the genus (i.e. a percentage identity to a particular SEQ ID NO), it would not be possible to determine from the sequence alone if the peptide is able directly or indirectly decreases the activity and/or expression of TREM-1 and treat Marfan Syndrome.
For claims 1-2, the specification does not describe a non-peptide molecule that can be used to treat Marfan Syndrome. For claims 4-16, the data do not suggest the physical basis for the TREM-1 inhibitory peptide activity and therefore do not describe which substitutions, deletions or additions could be made while preserving function of the disclosed peptides. The specification does not describe how the peptides operate to inhibit TREM-1 and treat Marfan Syndrome nor does it describe which residues are important for this function. Understanding the physical basis for TREM-1 inhibition and Marfan Syndrome treatment and the correlation between structure and function is critical to determining which of the countless sequences that meet the structural requirements of the genus also meet the functional requirements of the genus.
For these reasons, the skilled artisan would not reasonably conclude that the inventor(s), at the time the application was filed, had possession of the full scope of the claimed invention. In conclusion, only SEQ ID NOs: 2-11, satisfy the written description requirements of 35 U.S.C. 112(a).
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 1-2 and 4-16 are rejected under 35 U.S.C. 103 as being unpatentable over Gibot et al. (WO 2014/037565, IDS 9/22/2023) in view of Vandestienne et al. (NPL 1, IDS 9/22/2023) and Hagerty et al. (Abdominal Aortic Aneurysm in Marfan Syndrome. Anals of Vascular Surgery, 2017, 40, p. 294.c1-6).
Claim Interpretation
BRI of the claims includes a method of administering a therapeutically effective amount of a TREM-1 inhibitor to a patient with Marfan Syndrome, wherein the prior art purpose of the administration is to treat abdominal aortic aneurysm associated with Marfan Syndrome. This is embodiment is consistent with the definition of “treat” on page 4 of the specification, which includes prophylactic, preventative, curative, and disease modifying treatment. Treating abdominal aortic aneurysm associated with Marfan Syndrome constitutes a disease modifying treatment.
Determining the scope and contents of the prior art.
Gibot et al. teach peptides derived from Triggering receptor expressed on myeloid cells 1 (TREM-1) and TREM-like transcript 1 (TLT-1). The prior art peptides SEQ ID NOs: 3-7 and 9-12 (p. 7, Table 1) are identical to the instantly claimed TREM-1 inhibitor peptides SEQ ID NOs: 2-6 and 8-11, respectively. Gibot et al. teach that TREM-1- and TLT-1-derived peptides function as TREM-1 inhibitors and can be used in methods of treating cardiovascular diseases, including aneurysm (p. 14, lines 20 - p. 16, line 11). Gibot et al. teach pharmaceutical compositions comprising a therapeutically effective amount of the TREM-1 inhibitor peptides (p. 17, lines 5-27).
Gibot et al. teach that TREM-1 is expressed on endothelia cells from aortic and mesenteric artery (p. 38, Results 2; Figures 1A-B), expressed on lung and liver microvascular endothelial cells (p. 39, Results 3; Figures 3-5), and expressed in myocardial tissue and is upregulated during ischemia (p. 41, Results 5; Figure 10).
Gibot et al. reduce to practice several embodiments using the TREM-1 inhibitor peptides, including the peptide TLT1-L12 (SEQ ID NO: 4), which is identical to the elected species SEQ ID NO: 3. Gibot et al. teach that TREM-1- and TLT-1-derived peptides improve LPS-induced contractile and endothelial dysfunction in aorta (p. 38, Results 1; Figures 1A-C); improve sepsis-induced cardiovascular dysfunction (pp. 39-41, Results 4; Figures 6-9; Table 2); modulate leukocyte recruitment during myocardial infarction in mice and regulate leukocyte mobilization from remote compartments (p. 42, Results 6; Figure 11); modulate myocardial inflammatory reaction during myocardial infarction in mice (pp. 42-43, Results 7; Figures 12-13); decrease protease activity in myocardial infarcted tissue (pp. 43-44, Results 8; Figure 14); improve survival after myocardial infarction in mice (p. 44, Results 9; Figure 15); improve cardiac function after myocardial ischemia-reperfusion in rats (pp. 44-47, Results 10; Tables 3-4; Figure 16); improve systolic and diastolic functions after myocardial infarction in rats (pp. 47-48, Results 11; Table 5; Figure 17); prevent atherosclerosis development in mice (p. 49, Results 12; Figure 18); alter atheromatous plaque cellular composition (p. 49, Results 13; Figure 19); modify blood leukocytes population in atherosclerotic mice (p. 49, Results 14; Figures 20-21); and decrease monocyte recruitment to atherosclerotic plaques (p. 50, Results 15; Figure 22).
Ascertaining the differences between the prior art and the claims at issue.
Although Gibot et al. teach that TREM-1 inhibitor peptides can be used in methods of treating cardiovascular diseases in general, including aneurysm (p. 14, lines 20 - p. 16, line 11), Gibot et al. do not teach a method of treating Marfan Syndrome patients, including those suffering from or at risk of developing abdominal aortic aneurysm.
Resolving the level of ordinary skill in the pertinent art.
Hagerty et al. teach that patients with Marfan Syndrome are at risk for developing abdominal aortic aneurysm (abstract).
Vandestienne et al. explore the role of TREM-1 in abdominal aortic aneurysm (AAA) using a mouse model of angiotensin II-induced (AngII-induced) AAA (p. 2, col. 1, para. 2). Vandestienne et al. teach that TREM-1 expression was detected in mouse aortic aneurysm and colocalized with macrophages (p. 2, col. 1-2, bridging para; Figure 1). Vandestienne et al. teach that Trem1 gene deletion (Apoe-/-Trem1-/-) limited both AAA development and severity (p. 2, col. 1-2, bridging para; Figure 1). Vandestienne et al. teach that TREM-1 pharmacological blockade with LR-12 peptide, which is identical to instant SEQ ID NO: 3, also limited both AAA development and severity (pp. 2-3, bridging para.; Figure 2). Vandestienne et al. teach that in human AAA, TREM-1 was detected and TREM1 mRNA expression correlated with SELL mRNA expression, and that circulating levels of sTREM-1 were increased in patients with AAA when compared with patients without AAA (pp. 6-9, bridging paras.; Figure 6). Vandestienne et al. conclude that TREM-1 is involved in AAA pathophysiology and may represent a promising therapeutic target in humans (pp. 10-11, bridging para.).
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The specification demonstrates that TREM-1 is expressed by macrophages in the aortic wall of Marfan (Figure 1), that TREM-1 deficiency protects against aortic rupture in a mouse model of Marfan Syndrome (Figures 2-3), and that overstimulation of TREM-1 aggravates aorta rupture in Marfan mice (Figure 4) (pp. 13-14).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to administer a therapeutically effective amount of the TREM-1 inhibitor peptides taught by Gibot et al. to patients suffering from Marfan Syndrome and also suffering from or at risk of developing abdominal aortic aneurysm as taught by Hagerty et al. The rationale for obviousness is some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention (MPEP § 2143.01(G)). The relevant findings for this rationale are as follows.
(1) There was some teaching, suggestion, or motivation, either in the references themselves or in the knowledge generally available to one of ordinary skill in the art, to modify the reference or to combine reference teachings. In the instant case, one of ordinary skill in the art would have been motivated to use TREM-1 inhibitors to treat abdominal aortic aneurysm in Marfan Syndrome patients because Hagerty et al. teach that patients with Marfan Syndrome are at risk for developing abdominal aortic aneurysm (abstract) and are therefore in need of treatment. In seeking a suitable treatment, one of ordinary skill in the art would understand that Vandestienne et al. teach that TREM-1 is involved in abdominal aortic aneurysm pathophysiology and is a promising therapeutic target in humans (pp. 10-11, bridging para.). In seeking suitable agents that target TREM-1, one of ordinary skill in the art would understand that Godot et al. teach several specific TREM-1 inhibitor peptides that are therapeutically effective for cardiovascular diseases, including aneurysm, one of which is taught by Vandestienne et al. to reduce abdominal aortic aneurysm development and severity (pp. 2-3, bridging para.; Figure 2). Therefore, there was some teaching, suggestion, or motivation, either in the references themselves or in the knowledge generally available to one of ordinary skill in the art, to modify the reference or to combine reference teachings.
(2) There was reasonable expectation of success. One of ordinary skill in the art would predict that TREM-1 inhibitor peptides, such as those taught by Godot et al. and Vandestienne et al. would be suitable for use in a method of treating abdominal aortic aneurysm in Marfan Syndrome patients by TREM-1 inhibition because Vandestienne et al. teach that TREM-1 pharmacological blockade with LR-12 peptide, which is identical to instant SEQ ID NO: 3, reduced abdominal aortic aneurysm development and severity (pp. 2-3, bridging para.; Figure 2), and 2). Therefore, there was a reasonable expectation of success.
(3) Whatever additional findings based on the Graham factual inquiries may be necessary, in view of the facts of the case under consideration, to explain a conclusion of obviousness. The results in specification are consistent with, not unexpected, in view of the prior art teaching of Vandestienne et al.
The rationale to support a conclusion that the claim would have been obvious is that "a person of ordinary skill in the art would have been motivated to combine the prior art to achieve the claimed invention and whether there would have been a reasonable expectation of success in doing so." DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356, 1360, 80 USPQ2d 1641, 1645 (Fed. Cir. 2006).
Therefore, claims 1 and 4 are obvious over the cited art.
Regarding claim 2, although the references are silent with respect to the effect of TREM-1 inhibitor peptides on aortic rupture, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). In the instant case, the effect of TREM-1 inhibitor peptides on aortic rupture would occur as a result of administering the same compounds to the same patients in view of the combined references as required by the claims.
Regarding claim 5, Gibot et al. teach TREM-1 inhibitor peptides SEQ ID NOs: 3-7 and 9-12 (p. 7, Table 1), which are identical to the instantly claimed TREM-1 inhibitor peptides SEQ ID NOs: 2-6 and 8-11, respectively.
Regarding claims 6-10 and 15, the TREM-1 inhibitor peptides SEQ ID NOs: 3-7 (p. 7, Table 1), which are identical to the instantly claimed TREM-1 inhibitor peptides SEQ ID NOs: 2-6, respectively, are consecutive amino acid fragments from human TLT-1 (SEQ ID NO: 1, which is identical to instant SEQ ID NO: 12) are 17, 12, 6, 6, and 6 amino acid residues in length, respectively.
Regarding claims 11-14 and 16, the TREM-1 inhibitor peptides SEQ ID NOs: 9-12 (p. 7, Table 1), which are identical to the instantly claimed TREM-1 inhibitor peptides SEQ ID NOs: 8-11, respectively, are are consecutive amino acid fragments from human TREM-1 (SEQ ID NO: 2, which is identical to SEQ ID NO: 1) and are 12, 6, 6, and 6 amino acid residues in length, respectively.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTINA MARCHETTI BRADLEY whose telephone number is (571)272-9044. The examiner can normally be reached Monday-Friday, 7 am - 3 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lianko G Garyu can be reached at (571) 270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHRISTINA BRADLEY/Primary Examiner, Art Unit 1654
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