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
Claims 1-3, 8, 10-18, 23-31, 36-38, 40-61, 64, and 66-69 are pending.
Claims 55-61, 64, and 66-69 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, Group II, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on September 15, 2025.
Claims 1-3, 8, 10-11, 13, 23-31, 36-38, 40, 42, and 48-54 encompass SEQ ID NO: 6. SEQ ID NO: 6 was search and prior art was found. The search also yielded art on SEQ ID NO: 9, which is encompassed by claims 1-3, 8, 10-11, 16, 23-31, 36-38, 40, 45, and 48-54. Examination was not extended to the remaining species.
Claims 12, 14-15, 17-18, 41, 43-44, and 46-47 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claim Interpretation
BRI of the following claim terms is according to the definitions in the original specification:
abnormal vasculature at p. 28, lines 11-13;
therapeutically effective at p. 33, lines 16-32;
bolus at p. 34, lines 1-2;
vasculature normalization at p. 27, lines 9-13;
cytotoxic T-cells at p. 28, lines 18-19; and
natural kill cells, p. 28, lines 5-7.
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.
Issues Relevant to Both Written Description and Enablement Presented Once for Brevity
1) Scope of the Claims
Claim 1 is a method of treating a subject having an abnormal vasculature in any tissue or organ. Claim 2 is a method of increasing a number of cytotoxic T-cells or activated NK cells in a subject in need thereof. The scope of the subject of both methods encompasses subjects with cancer in view of at p. 28, lines 5-19. Claim 38 is a method of treating cancer.
BRI of the claims includes subjects with cancer and is not limited to any particular type of cancer. The methods utilize a bolus dose
U-GLSKGCFGLKLDRIGSMSGLGC [SEQ ID NO. 2], wherein U is (aliphatic)a-(X)- wherein
a is 1;
aliphatic is an optionally substituted C4-24 chain covalently bound to X via a chemical linkage, comprising a carbonyl, a thioether, an ether, a thioether, a carbamate moiety, or carbon to carbon bond;
X is a 1-10 amino acid residue or peptide sequence, wherein each amino acid residue is independently selected from lysine (K), arginine (R), glycine (G), alanine (A), glutamic acid (E), and aspartic acid (D); or X is a linker (γE)m-(B)n wherein B is 1-8 amino acid residue or peptide sequence wherein each amino acid residue is independently selected from 2-[2-(2-aminoethoxy)ethoxy]acetic acid residue, Gly, Ala, Leu, Ser, Arg, and Lys; m is 0, 1, 2, or 3; n is 0, 1, 2, or 3; and the sum of m and n is at least 1; and
Only those sequences meeting the structural and functional requirements of the genus are encompassed by the claim. Therefore, the claim encompasses all of the peptide structures meeting the structural requirements above that are also able to when administered in a bolus dose provide vascular normalization or an increase in pericyte coating index of at least 10% (claim 1), provide an increase in the number of cytotoxic T cells and/or NK cells of at least 15% above the level prior to administration (claim 2), and not decrease blood pressure by more than 15% of a baseline blood pressure measurement; and wherein the composition increases plasma cyclic-GMP level at from 1 hour to 12 hours of a baseline plasma cyclic-GMP level, and the baseline plasma cyclic-GMP level is an average plasma cyclic-GMP level prior to administration of the composition or the average plasma cyclic-GMP level of a healthy subject (claim 38).
2) Actual Reduction to Practice
Despite the breadth of the claims with respect to the CNP compounds, Examples 1-29 pertain to a single species SEQ ID NO: 6 as a long-acting CNP derivative and/or a single species SEQ ID NO: 6 formulated with a single pharmacokinetic (PK) extending excipient as a very long-acting CNP derivative. The PK extending excipient is 25 kDa polylysine grafted with 5 kDa polyetheylene glycol (PEG) at the epsilon amino groups of the linear polylysine backbone. Only Example 30 discloses additional species, SEQ ID NOs: 20 and 21 and in that example only pharmacokinetics are evaluated.
Example 1 shows that a single long-acting CNP, SEQ ID NO: 6, and a single very long-acting CNP, SEQ ID NO: 6 formulated with a single pharmacokinetic (PK) extending excipient at a CNP: excipient weight ratio of 1:10 showed significant elevation of cyclic-GMP for at least 24 hours after bolus subcutaneous administration.
Example 2 shows SEQ ID NO: 6 formulated with the PK extending excipient can increase plasma cyclic-GMP without a drop in blood pressure after bolus subcutaneous administration.
Example 25 shows SEQ ID NO: 6 activates the immune system as seen by an increase in T-cells, specifically cytotoxic (CD8) T-cells and natural killer (NK) cells in blood and CD8, CD4, ICOS, and CD86 gene expression in spleen after administration in healthy subjects.
Example 30 shows the pharmacokinetic profile of two additional species HOC(=O)(CH2)16C(=O)-Aeea-Aeea-GCFGLKLDRIGShomoQSGLGC (SEQ ID NO. 21), and HOC(=O)(CH2)16C(=O)-γE-Aeea-Aeea-GCFGLKLDRIGShomoQSGLGC (SEQ ID NO. 20), each with a disulfide bond between the 2 cysteine residues.
Despite the breadth of the claims with respect to subjects having cancer, only a single long-acting CNP, SEQ ID NO: 6, and a single very long-acting CNP, SEQ ID NO: 6 formulated with a single pharmacokinetic (PK) extending excipient, are evaluated only in breast cancer (Examples 3-5, 9-11, 16-20, and 26-28), colon cancer (Examples 12-14), osteosarcoma (Examples 6-8 and 21-22), prostate cancer (Examples 23-24 and 29), and melanoma (Example 15).
Example 3 shows SEQ ID NO: 6 formulated with the PK extending excipient increased cluster of differentiation 8 positive (CD8+) T cell in breast tumor.
Example 4 shows SEQ ID NO: 6 formulated with the PK extending excipient increased activated T cell in breast tumor.
Example 5 shows SEQ ID NO: 6 formulated with the PK extending excipient eradicated regulatory T cell in breast tumor allowing the immune system to suppress tumor growth.
Example 6 shows that the anti-tumor of SEQ ID NO: 6 formulated with the PK extending excipient in bone tumor is directly related to CD8 activation.
Examples 7 and 8 show that SEQ ID NO: 6 formulated with the PK extending excipient suppressed the size of growth of bone cancer.
Example 9-11 show that SEQ ID NO: 6 formulated with the PK extending excipient normalized breast cancer tumor vascular structure and reduced hypoxia.
Examples 12-13 show SEQ ID NO: 6 formulated with the PK extending excipient combined with anti-mouse cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody therapy greatly suppressed growth of colon cancer.
Example 14 shows SEQ ID NO: 6 formulated with the PK extending excipient combined with anti-mouse Programmed cell death protein 1 (PD-1) antibody therapy greatly suppressed growth of colon cancer.
Example 15 shows SEQ ID NO: 6 formulated with the PK extending excipient combined with anti-mouse cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody therapy greatly suppressed growth of melanoma.
Examples 16-20 show SEQ ID NO: 6 formulated with the PK extending excipient combined with anti-mouse Programmed cell death protein 1 (PD-1) antibody therapy greatly suppressed growth of breast cancer and improve survival.
Example 21 shows SEQ ID NO: 6 formulated with the PK extending excipient combined improved survival in osteosarcoma
Example 22 shows SEQ ID NO: 6 enhances LM8-elicited IFNg production in splenocytes.
Examples 23-24 show SEQ ID NO: 6 suppresses prostate cancer growth and that the effect is mediated by CD8 activity
Example 26 shows a synergistic effect between SEQ ID NO: 6 formulated with the PK extending excipient and an anti-PD1 antibody in increasing Th1 cells and decreasing Treg cells of the immune system in mice with breast cancer.
Example 27 shows that the adjuvant CpG oligodeoxynucleotides, a Toll-like receptor-9 agonist, enhanced the breast cancer tumor suppression of SEQ ID NO: 6.
Example 28 shows SEQ ID NO: 6, an anti-PD-1 antibody, and a combination thereof decrease tumor volume and Treg cells and increase CD69+ cells in breast cancer.
Example 29 shows SEQ ID NO: 6 suppressed expression of fibrosis-associated and vascular-disrupting genes within prostate cancer.
3) State of the Prior Art, Ordinary Skill in the Art and Level of Predictability in the Art
There is a high level of unpredictability and complexity associated with the structure-activity relationship of natriuretic peptides including CNPs. Castillo et al. (WO 2018/175534 A1) teach that natriuretic peptides increase cyclic guanosine monophosphate (cyclic-GMP) and can be used to treat a variety of vascular and cardiovascular diseases and conditions (p. 1). Castillo et al. identified a problem in the prior art: medicinal use of natriuretic peptides including C-type natriuretic peptide (CNP) is limited by their short half-life, limited activity to provide sufficient cyclic-GMP, and requirement for continuous intravenous administration (p. 2, lines 2-5). To solve this problem, Castillo et al. developed natriuretic peptides with extended half-lives and enhanced activity as measured by an increase in cyclic-GMP (p. lines 24-27).
Castillo et al. teach (pp. 9-10, bridging para.): “It is believed that alteration of amino acid sequence of peptides can have unpredictable consequences on their biological activity, and alterations that preserve peptide activity is not obvious and [is] unpredictable. The present disclosure describes specific structural alterations of naturally occurring natriuretic peptide (NP)…. Briefly, specific alterations of parent NP resulted in surprisingly unexpected enhancement or increased potency compared to the parent NP in vivo as measured by blood cGMP response, while other alterations resulted in loss of activity.”
In addition, there is a high level of unpredictability and complexity associated with bolus administration of CNP because of its short half-life (2-13 minutes), and the fact that bolus administration is associated with an acute drop in blood pressure. See, e.g., Kimura et al., J Surg Res. 2015, 194(2); 631-637, cited by Applicant.
In addition, there is a high level of unpredictability and complexity associated with using CNP to treat cancer. Cell culture studies have shown that CNP did not inhibit growth of small-cell lung cancer cells (see, e.g., Vesely et al., Eur J Clin Invest 2005, 35(1), 60-69) and breast adenocarcinoma cells (see, e.g., Vesely et al., Eur J Clin Invest 2005, 35(6), 388-398); and at 1 μM had no anti-cancer effects in general (see, e.g., Vesely. Curr Pharm Des., 2010, p 1159-1166; U.S. Pat. No. 7,846,900) (all cited by Applicant). In addition, the original specification states at p. 6, lines 3-10: “CNP is known to elevate intracellular cyclic-GMP, and elevation of intracellular cyclic-GMP protects cells from apoptotic death and is thus contrary to the objectives in cancer treatment.” In addition, other studies (see, e.g., U.S. Pat. No. 9,759,725, cited by Applicant) describe inhibiting CNP production to treat cancer, and thus is contrary to using guanylate cyclase C agonists such as CNP to destroy cancer cells. Kanagawa et al. (EP 3189835 B1) teach methods of suppressing the metastasis of malignant tumors using natriuretic peptide receptor GC-B agonists that function by elevating the vascular endothelial intracellular cGMP levels, including c-type natriuretic peptide via continuous infusion (CNP) (para. [0001], [0008, Example 13). Likewise, for the CNP treatment of rhabdomyosarcoma tumor bearing mice, CNP must be administered by infusion at a slow rate of 2.5 ug/kg/min for 4 weeks (see, e.g., Zenitani et al., Cancer Med., 2016 5(5) p 795-805, cited by Applicant) rather than a bolus dose; with limited efficacy.
Written Description Rejection
Claims 1-3, 8, 10, 23-31, 36-38, and 48-54 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.
Only the long-acting CNP derivative SEQ ID NO: 6 and the very long-acting CNP derivative SEQ ID NO: 6 formulated with 25 kDa polylysine grafted with 5 kDa polyetheylene glycol (PEG) at the epsilon amino groups of the linear polylysine backbone were reduced to practice for treating subjects with breast, colon, and prostate cancer, osteosarcoma, and melanoma. The species SEQ ID NOs: 20 and 21 were evaluated in a pharmacokinetic study only. As discussed above the claim scope is enormous given the breadth of structural limitations and complexity of functional limitations in the claims. Therefore, one of ordinary skill in the art would not consider SEQ ID NO: 6 with and without the polymer, and SEQ ID NOs: 20 and 21 to be representative of the full scope of the claimed genus. 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 complete structure of SEQ ID NOs: 5 and 7-9 which are very closely related to SEQ ID NOs: 6, 20, and 21.
The data presented in the specification raise more questions about the physical properties of the genus than they answer. The data do not suggest the physical basis for the claimed activity and therefore do not describe which substitutions, deletions or additions could be made while preserving function. Understanding the physical basis for the claimed activity is critical to determining which of the sequences that meet the structural requirements of the genus also meet the functional requirements of the genus.
The specification does not describe a general correlation between structure and function for the claimed genus. The role of the 22 amino acids of CNP in receptor binding, pharmacokinetics, cGMP elevation, blood pressure regulation, cytotoxic T-cell and ANK cell activation, and cancer treatment are not described. As a result, it is impossible to predict, based on the specification, how changing any position will affect the claimed functions.
As described above there is a high degree of unpredictability in the prior art with respect to CNP structure-function, CNP bolus administration, the effect of CNP on blood pressure, and the use of CNP to treat cancer. For all of the reasons presented above, one of ordinary skill in the art would not know which of the countless peptides that meet the structural requirements of the claims would also be able to perform the complicated claimed functions. The specification does not make clear which peptides are in the genus and which are not because it does not describe the physical basis for the claimed activity. In other words, the specification does not describe which peptides to make.
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: 5-9, 20 and 21, satisfy the written description requirements of 35 U.S.C. 112(a).
Response to Arguments
In the response filed February 23, 2026, Applicant traversed the written description rejection on the grounds that the specification supports the amended claims. However, the response does not address how the specification supports the full scope of the use of the narrowed genus of compositions, that is the full scope of the methods with respect to the subject, which may have any type of cancer. Applicant argues that the unpredictability in the art pertains to intracellular cGMP concentrations, which is addressed by Figure 2 of the specification. However, the art shows that changes in the amino acid sequence of CNP can affect activity. Although the claims have been narrowed, there is still significant breadth in the amino acid sequence owing to variable X. In addition, the rejection is also based on the level of unpredictability with respect to cancer, which has not been addressed. The specification does not establish that Applicant was in possession of the full scope of the claimed methods, particularly in any subject in need thereof, which includes a subject with any type of cancer. For these reasons, the rejection is maintained.
Enablement Rejection
Claims 1-3, 8, 10-11, 13, 16, 23-31, 36-38, 40, 42, 45, and 48-54 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 using the long-acting CNP derivative SEQ ID NO: 6 and the very long-acting CNP derivative SEQ ID NO: 6 formulated with 25 kDa polylysine grafted with 5 kDa polyetheylene glycol (PEG) at the epsilon amino groups of the linear polylysine backbone for treating subjects with breast, colon, and prostate cancer, osteosarcoma, and melanoma, does not reasonably provide enablement for all other CNPs and uses. 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).
Factors (3)-(8) are discussed above.
Only the long-acting CNP derivative SEQ ID NO: 6 and the very long-acting CNP derivative SEQ ID NO: 6 formulated with 25 kDa polylysine grafted with 5 kDa polyetheylene glycol (PEG) at the epsilon amino groups of the linear polylysine backbone were reduced to practice for treating subjects with breast, colon, and prostate cancer, osteosarcoma, and melanoma. As discussed above the claim scope is enormous given the breadth of structural limitations and complexity of functional limitations in the claims. Therefore, one of ordinary skill in the art would not consider SEQ ID NO: 6 with and without the polymer treating subjects only with breast, colon, and prostate cancer, osteosarcoma, and melanoma to be representative of the full scope of the claimed methods with respect to subject and application and to CNP administered.
The guidance in the specification is extremely limited. The data do not suggest the physical basis for the claimed activity and therefore do not describe which substitutions, deletions or additions could be made while preserving function. The specification does not describe a general correlation between structure and function for the claimed genus. The role of the 22 amino acids of CNP in receptor binding, pharmacokinetics, cGMP elevation, blood pressure regulation, cytotoxic T-cell and ANK cell activation, and cancer treatment are not described. As a result, it is impossible to predict, based on the specification, how changing any position will affect the claimed functions.
As described above there is a high degree of unpredictability in the prior art with respect to CNP structure-function, CNP bolus administration, the effect of CNP on blood pressure, and the use of CNP to treat cancer. For all of the reasons presented above, one of ordinary skill in the art would be burdened with extensive experimentation to practice the claimed methods.
Therefore, in view of the Wands factors, the claims appear to require undue experimentation to use the full scope of the claimed invention.
Response to Arguments
In the response filed February 23, 2026, Applicant traversed the enablement rejection on the grounds that the specification supports the amended claims. However, the response does not address how the specification supports the full scope of the use of the narrowed genus of compositions, that is the full scope of the methods with respect to the subject, which may have any type of cancer. There would be an undue burden of experimentation required to use the claimed compositions to achieve the claimed effects in any subject in need thereof, including a subject with any type of cancer. For these reasons, the rejection is maintained.
Claim Rejections - 35 USC § 112(b) - withdrawn
The rejection of claims 5-10, 22, 27, 38-39, and 48 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in view of the amendment filed February 23, 2026.
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.
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, 8, 10-11, 13, 16, 23-25, 27-28, 36-38, 40, 42, 45, and 49-54 are rejected under 35 U.S.C. 103 as being unpatentable over Kanagawa et al. (EP 3189835 B1) in view of Castillo et al. (WO 2018/175534 A1).
The factual inquiries for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) 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.
Determining the scope and contents of the prior art.
Kanagawa et al. teach methods of suppressing the metastasis of malignant tumors using natriuretic peptide receptor GC-B agonists that function by elevating the vascular endothelial intracellular cGMP levels, including c-type natriuretic peptide (CNP) (para. [0001], [0008). The specific teaching of this reference maps to independent claims 1, 2, and 38 as follows:
Claim 1
Claim 2
Claim 38
Primary Reference
A method of treating a subject having abnormal vasculature in any tissue or organ
A method of increasing a number of cytotoxic T-cells and/or a number of activated NK cells
A method of treating a subject having cancer
Kangawa et al. teach a method for suppressing malignant tumor metastasis (para. [0017]-[0019).
comprising administering to the subject
comprising administering to a subject in need thereof
comprising administering to a subject in need thereof
BRI of a subject having abnormal vasculature of claim 1 and BRI of a subject in need of increasing a number of cytotoxic T-cells and/or number of activated NK cells of claim 2 includes subjects having cancer (see original specification, p. 22).
Kangawa et al. teach a method for suppressing malignant tumor metastasis comprising administering a CNP to a subject having melanoma, which is a subject having cancer (Example 13).
Therefore, Kangawa et al. teaches a subject that falls within the genus of the subjects in claims 1, 2, and 38, a subject with melanoma.
a therapeutically effective bolus dose of a composition comprising U-GLSKGCFGLKLDRIGSMSGLGC [SEQ ID NO. 2], wherein U is (aliphatic)a-(X)
a therapeutically effective bolus dose of a composition comprising U-GLSKGCFGLKLDRIGSMSGLGC [SEQ ID NO. 2], wherein U is (aliphatic)a-(X)
a therapeutically effective bolus dose of a composition comprising U-GLSKGCFGLKLDRIGSMSGLGC [SEQ ID NO. 2], wherein U is (aliphatic)a-(X)
Kangawa et al. teach that the CNP is administered in a continuous dose in a therapeutically effective amount to suppress melanoma metastasis (Example 13). Kanagawa et al. teach that the CNP is hCNP-22, which is GLSKGCFGLKLDRIGSMSGL GC (SEQ ID NO: 7), wherein the two cysteines for a disulfide bond (¶ [0057-[0058]). Kanagawa et al. teach that the dose is 2.5 mg/kg/min delivered continuously by an osmotic pump subcutaneously implanted (¶ [0185]).
As shown in Figs. 18 and 19, CNP significantly suppressed the metastasis of melanoma as compared with the control group (¶ [0185]).
wherein administering the therapeutically effective bolus dose of the composition provides a vasculature normalization or an increase in pericyte coating index by at least 10%.
wherein the therapeutically effective bolus dose of the composition provides an increase in the number of cytotoxic T cells and/or NK cells of at least 15% above the level prior to administration of the composition or above the level in a healthy subject.
wherein the composition does not decrease blood pressure by more than 15% of a baseline blood pressure measurement, and wherein the composition increases plasma cyclic-GMP level at from 1 hour to 12 hours after administration to above 1 .5x of a baseline plasma cyclic-GMP level, and the baseline plasma cyclic-GMP level is an average plasma cyclic-GMP level prior to administration of the composition or the average plasma cyclic-GMP level of a healthy subject.
Kangawa et al. teach that CNP increases intracellular cyclic-GMP (¶ [0013]).
Ascertaining the differences between the prior art and the claims at issue.
Kangawa et al. do not teach: 1) bolus administration, 2) that the CNP is U-GLSKGCFGLKLDRIGSMSGLGC [SEQ ID NO. 2], wherein U is (aliphatic)a-(X), or 3) the precise effect of administration on cyclic-GMP levels, blood pressure, vasculature normalization, and the number of cytotoxic T cells and/or NK cells recited in the instant claims.
Resolving the level of ordinary skill in the pertinent art.
It is within the ordinary level of skill in the pertinent art to use long-acting and very long-acting CNPs for therapeutic applications.
Castillo et al. teach that natriuretic peptides increase cyclic guanosine monophosphate (cyclic-GMP) and can be used to treat a variety of vascular and cardiovascular diseases and conditions (p. 1). Castillo et al. identified a problem in the prior art: medicinal use of natriuretic peptides including C-type natriuretic peptide (CNP) is limited by their short half-life, limited activity to provide sufficient cyclic-GMP, and requirement for continuous intravenous administration (p. 2, lines 2-5). To solve this problem, Castillo et al. developed natriuretic peptides with extended half-lives and enhanced activity as measured by an increase in cyclic-GMP (p. lines 24-27). The natriuretic peptides can be administered by parenteral routes, including subcutaneous bolus administration (p. 3, lines 16-23; Example 1).
Castillo et al. teach a long-acting CNP with the structure CH3(CH2)16COKKKKGGGGLSKGCFGLKLDRIGSMSGLGC (compound 72; p. 42), which is identical to elected species instant SEQ ID NO: 6. SEQ ID NO: 6 is CH3(CH2)16C(=O)KKKKGGGGLSKGCFGLKLDRIGSMSGLGC, which is CNP derivative in the genus of claim 38 comprising SEQ ID NO: 2 (underlined) wherein U is a moiety of Formula (I) (aliphatic)a-(X), wherein a is 1, aliphatic is a C18 chain covalently bound to X by a carbonyl as part of an amide linkage, X is a seven amino acid peptide sequence KKKKGGG wherein each amino acid is K or G and a linker (gE)m-(B)n wherein m is 0, B is a seven amino acid peptide sequence KKKKGGG wherein each amino acid is K or G, and n is 1.
In addition, Castillo et al. teach CH3(CH2)22COKKKKGGGGLSKGCFGLKLDRIGSMSGLGC (compound 122; p. 42), which is identical to species instant SEQ ID NO: 9.
Castillo et al. teach that this compound has “unexpectedly increased potency” and “prevented apparent receptor depletion/internalization” (p. 39, lines 1-9). The CNP 72 (instant SEQ ID NO: 6) has the highest level of activity at 2 hours and 6 hours compared to hCNP (compound 57) of the derivatives tested by Castillo et al. (see data on p. 42; the activity columns show data at 2 hours and 6 hours) and compound 122 (instant SEQ ID NO: 9) also has high activity:
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Castillo et al. teach a method of increasing blood cGMP in a patient comprising parenterally or subcutaneously administering the natriuretic peptide at a dose of less than 1.5 mg/kg/day of body weight in a pharmaceutically acceptable carrier or excipient (p. 28, lines 8-20). Single injections were reduced to practice, which constitutes a bolus dose (Example 1, p. 35, lines 8-10).
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The specification does not provide a comparison between hCNP-22 and SEQ ID NO: 6 and SEQ ID NO: 9 in a melanoma metastasis model.
It would have been obvious to one of ordinary skill before the effective filing date of the claimed invention to substitute bolus administration of the long-acting CNP identical to instant SEQ ID NO: 6 or 9 taught by Castillo et al. for the continuous administration of hCNP-22 in the method of suppressing melanoma metastasis taught by Kangawa et al. The rationale for obviousness is simple substitution of one known element for another to obtain predictable results (MPEP § 2143.01(B)). The relevant findings for this rationale are as follows.
(1) The prior art contained a device (method, product, etc.) which differed from the claimed device by the substitution of some components (step, element, etc.) with other components. In the instant case, the primary reference of Kangawa et al. teaches a method of suppressing melanoma metastasis comprising continuous administration of hCNP-22 which differs from the claimed method by the substitution of continuous administration of hCNP-22 with bolus administration of long-acting CNP SEQ ID NO: 6. Therefore, prior art contained a method which differed from the claimed device by the substitution of some step with other steps.
(2) The substituted components and their functions were known in the art. Castillo et al. teach SEQ ID NO: 6 and 9 and its administration to a subject by a bolus dose, which is the substituted component. The function of SEQ ID NO: 6 and 9 is known in the art because Castillo et al. teach that this compound has “unexpectedly increased potency” and “prevented apparent receptor depletion/internalization” (p. 39, lines 1-9). Castillo et al. provide a direct comparison between hCNP-22 (compound 57 in Castillo et al.) and SEQ ID NO: 6 (compound 72 in Castillo et al.): SEQ ID NO: 6 has significantly increased potency at 2 hours as well as at 6 hours (p. 42, Table reproduced above). SEQ ID NO: 9 (compound 122) also has high potency. Therefore, the substituted components and their functions were known in the art.
(3) One of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have been predictable. One of ordinary skill in the art would expect that the long-acting CNP SEQ ID NO: 6 or 9 performs the function of elevating intracellular cyclic-GMP in the combination because Castillo et al. demonstrate by direct comparison to hCNP-22 that SEQ ID NO: 6 and 9 has this function in vivo and in fact has enhanced potency relative to hCNP-22. The hCNP-22 and SEQ ID NO: 6 and 9 (compounds 57 and 72 and 122 of Castillo et al.) share the same core CNP sequence. SEQ ID NO: 6 (compound 72) is modified at the N-terminus with an amino acid sequence KKKKGGG and a fatty acid CH3(CH2)16C=O. SEQ ID NO: 9 (compound 122) is modified at the N-terminus with an amino acid sequence KKKKGGG and a fatty acid CH3(CH2)22C=O. The N-terminal modification with the CH3(CH2)16C=O KKKKGGG or CH3(CH2)22C=O KKKKGGG is responsible for the increased potency, extended activity, and suitability for bolus administration. In view of the data from a direct comparison provided by Castillo et al., one of ordinary skill in the art would have a reasonable expectation that SEQ ID NO: 6 (compound 72) and SEQ ID NO: 9 (compound 122) would be effective in the method of Kanagawa et al., the method of suppressing metastasis in melanoma patients (Example 13). In addition, one of ordinary skill in the art would expect based on the direct comparison and the reduction to practice in Castillo et al. that the SEQ ID NO: 6 (compound 72) and SEQ ID NO: 9 (compound 122) would have the benefit of being long-acting and being suitable for bolus administration. Therefore, one of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have been predictable.
(4) 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 specification does not provide a comparison between hCNP-22 and SEQ ID NO: 6 and SEQ ID NO: 9 in a melanoma metastasis model. Therefore, there is no evidence of unexpected results sufficient to overcome the prima facie case.
The rationale to support a conclusion that the claim would have been obvious is that the substitution of one known element for another yields predictable results to one of ordinary skill in the art.
Regarding the precise effect of administration on cyclic-GMP levels, blood pressure, vasculature normalization, and the number of cytotoxic T cells and/or NK cells recited in the instant claims 1, 2, and 38, 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). The combination of cited art renders obvious the administration of SEQ ID NO: 6 to a subject with melanoma by bolus administration for the reasons presented above. The effect on cyclic-GMP levels, blood pressure, vasculature normalization, and the number of cytotoxic T cells and/or NK cells recited in the instant claims 1, 2, and 38 would occur as a result of this method because the method comprises administering the same compound, to the same subjects, in the same manner as the claimed method.
Therefore, claims 1, 2, and 38 are obvious over the cited art.
Regarding claims 8, 10-11, 13, 40, and 42, SEQ ID NO: 6 is CH3(CH2)16C(=O)KKKKGGGGLSKGCFGLKLDRIGSMSGLGC, which is CNP derivative comprising SEQ ID NO: 2 (underlined) wherein U is a moiety of Formula (I) (aliphatic)a-(X), wherein a is 1, aliphatic is a C18 chain covalently bound to X by a carbonyl as part of an amide linkage, X is a seven amino acid peptide sequence KKKKGGG wherein each amino acid is K or G and a linker (gE)m-(B)n wherein m is 0, B is a seven amino acid peptide sequence KKKKGGG wherein each amino acid is K or G, and n is 1.
Regarding claims 16 and 45, Castillo et al. also teach SEQ ID NO: 9 (compound 122).
Regarding claim 23, Castillo et al. teach bolus administration via a subcutaneous route (p. 3, lines 16-23; Example 1; p. 35, lines 8-10).
Regarding claims 24-25 and 27-28, Kangawa et al. that the subjects have melanoma (Example 13).
Regarding the precise effect of administration on blood pressure, vasculature normalization, pericyte coating index, tumor size, survival, the number of cytotoxic T cells and/or NK cells recited in the instant claims 36-37 and 49-54, 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). The combination of cited art renders obvious the administration of SEQ ID NO: 6 to a subject with melanoma by bolus administration for the reasons presented above. The effect on blood pressure, vasculature normalization, pericyte coating index, tumor size, survival, the number of cytotoxic T cells and/or NK cells recited in the instant claims 36-37 and 49-54 would occur as a result of this method because the method comprises administering the same compound, to the same subjects, in the same manner as the claimed method. Therefore, claims 36-37 and 49-54 are obvious over the cited art.
Claims 3, 26, and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Kanagawa et al. (EP 3189835 B1) in view of Castillo et al. (WO 2018/175534 A1), as applied to claims 1-2, 8, 10-11, 13, 16, 23-25, 27-28, 36-38, 40, 42, 45, and 49-54 above, in further view of Khair et al. (Combining Immune Checkpoint Inhibitors: Established and Emerging Targets and Strategies to Improve Outcomes in Melanoma. Front Immunol. 2019 Mar 19;10:453).
Regarding claims 3, neither Kanagawa et al. nor Castillo et al. teach that the melanoma subjects have a low number of cytotoxic T cells and/or activated NK cells.
Khair et al. teach that melanoma tumors have numerous mechanisms by which they escape immune destruction and suppress immune activity including via T-reg which expresses cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and which in turn acts as a negative regulator of effector T cell (T-eff) activity in vivo, and via Programmed-death ligand 1 (PD-L1; B7-H1; CD274), known to trigger T cell apoptosis (Figure 1).
Therefore, Khair et al. evidence that melanoma, the subject of Kanagawa et al. is characterized as having low cytotoxic T-cells, satisfying claims 3.
Regarding claim 26, neither Kanagawa et al. nor Castillo et al. teach that the melanoma is responsive to an immunostimulant. Regarding claim 29, neither Kanagawa et al. nor Castillo et al. teach further administrating an immune adjuvant to treat the melanoma.
Khair et al. teach inhibitors to CTLA-4 and the PD-1/PD-L1 axis are well-established for the clinical management of melanoma (abstract). These include ipilimumab, nivolumab, and pembrolizumab as FDA-approved therapies (Table 1).
MPEP § 2144.06(I) states: "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).
In the instant case, it would have been obvious to combine the CNPs taught by Kangawa et al. and Castillo et al. with the inhibitors to CTLA-4 and the PD-1/PD-L1 axis such as ipilimumab, nivolumab, and pembrolizumab taught by Forsberg et al. because both were taught to be useful for the same purpose of treating melanoma.
Claim 30 is rejected under 35 U.S.C. 103 as being unpatentable over Kanagawa et al. (EP 3189835 B1) in view of Castillo et al. (WO 2018/175534 A1), as applied to claims 1-2, 8, 10-11, 13, 16, 23-25, 27-28, 36-38, 40, 42, 45, and 49-54 above, in further view of Forsberg et al. (HER2 CAR-T Cells Eradicate Uveal Melanoma and T-cell Therapy-Resistant Human Melanoma in IL2 Transgenic NOD/SCID IL2 Receptor Knockout Mice. Cancer Res. 2019 Mar 1;79(5):899-904).
Regarding claim 30, neither Kanagawa et al. nor Castillo et al. teach further administrating CAR T-cells to treat the melanoma.
Forsberg et al. teach that CAR-T cells directed against HER2 can kill uveal and cutaneous melanoma cells in vitro and in vivo (abstract).
MPEP § 2144.06(I) states: "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).
In the instant case, it would have been obvious to combine the CNPs taught by Kangawa et al. and Castillo et al. with the Car-T therapy taught by Forsberg et al. because both were taught to be useful for the same purpose of treating melanoma.
Claim 48 are rejected under 35 U.S.C. 103 as being unpatentable over Kanagawa et al. (EP 3189835 B1) in view of Castillo et al. (WO 2018/175534 A1), as applied to claims 1-2, 8, 10-11, 13, 16, 23-25, 27-28, 36-38, 40, 42, 45, and 49-54 above, in further view of Bogdanov et al. (Protected Graft Copolymer (PGC) in Imaging and Therapy: A Platform for the Delivery of Covalently and Non-Covalently Bound Drugs. Theranostics. 2012;2(6):553-76) and Castillo et al. (Extending Residence Time and Stability of Peptides by Protected Graft Copolymer (PGC) Excipient: GLP-1 Example. Pharm Res (2012) 29:306–318; cited by Applicant).
Regarding claim 48, neither Kanagawa et al. nor Castillo et al. (WO 2018/175534 A1) teach that the long-acting CNP is combined with a polymer excipient comprising a poly(amino acid) grafted with PEG, fatty acid, anionic moieties, or any combination thereof.
Bogdanov et al. teach the family of protected graft copolymers (PGC) is based on a conjugate of polylysine backbone to which methoxypoly(ethylene glycol) (MPEG) chains are covalently linked in a random fashion via N-[Symbol font/0x65]-amino groups PGC is capable of long circulation times after injection into the blood stream. Bogdanov et al. teach that the PGC can bind natriuretic peptides and be used to deliver natriuretic peptides and extend their half-life (Section 5.3.2).
Castillo et al. teach a PGC excipient, polylysine was grafted with methoxypolyethyleneglycol and fatty acid at the epsilon amino groups (abstract). Castillo et al. that the PGC can bind the peptide GLP1 and can be used to deliver GLP1 and extend its half-life (abstract).
It would have been obvious to improve the half-life of the CNPs taught by Kanagawa et al. and Castillo et al. (WO 2018/175534 A1), including SEQ ID NO: 6 (aka compound 72) by combining it with the PGC excipients taught by Bogdanov et al. and Castillo et al. The resulting compositions would satisfy all of the limitations of claims 31-32 and 48 because the references teach that the poly(amino acid) polylysine is grafted with MPEG and a fatty acid, and that the excipient binds to the peptide for delivery and half-life extension. One of ordinary skill in the art would have been motivated to do so because Bgdanov et al. and Castillo et al. teach that PGC excipients are a solution to the problem of short half-lives that limit the use of the peptide drugs and that Castillo et al. (WO 2018/175534 A1) teach that this is a problem for CNP in particular (p. 2, lines 2-5). There would have been a reasonable expectation of success given that Bogdanov et al. teach that the PGC can bind natriuretic peptides and be used to deliver natriuretic peptides and extend their half-life (Section 5.3.2).
Response to Arguments
In the response filed February 23, 2026, Applicant traversed the rejection on the grounds that the specification provides evidence of unexpected results, namely that the results shown in FIG. 1A show a significant improvement in the increase in the plasma CNP for the claimed compositions compared to wild-type CNP with bolus administration. This argument has been full considered but is not persuasive.
In contrast to Applicant’s assertion that this result is unexpected in view of the cited art, one of ordinary skill in the art would expect this effect because Castillo et al. demonstrate by direct comparison to hCNP-22 that SEQ ID NO: 6 and 9 has enhanced potency relative to hCNP-22.
MPEP 716.02(b) states: The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992).
In the instant case, Applicant has not shown how the increase in the plasma CNP observed in FIG. 1A has a practical significance with respect to the claimed methods and is unexpected in view of the comparison provided in Castillo et al.
MPEP 716.02(d) states that the unexpected results must be commensurate in scope with the claimed invention.
In the instant case, Applicant has not explained how the relied upon evidence is commensurate in scope with the claims, which include administering a broad genus of subjects in need thereof, including subjects with any type of cancer.
MPEP 716.02(e) states that relied upon evidence “must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979).”
In the instant case, the specification does not provide a comparison between hCNP-22 and SEQ ID NO: 6 and SEQ ID NO: 9 in a melanoma metastasis model, as taught in the closest cited art.
For these reasons, the rejection is maintained.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/CHRISTINA BRADLEY/Primary Examiner, Art Unit 1654