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 without traverse of the species CH3(CH2)16C(=O)KKKKGGGGLSKGCFGLKLDRIGSMSGLGC (SEQ ID NO: 6) in the reply filed on December 30, 2025, is acknowledged.
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. Note that SEQ ID NO: 6 is not a species of the subgenus wherein U is Formula II containing a polymer selected from cellulose, PEG, mPEG or poly(N-vinylpyrolidone). Note that SEQ ID NO: 6 is not a long acting NPRB agonist as defined on p. 28 of the specification because it contains the 22 amino acid residue CNP sequence.
Therefore, claims 1-2, 4-8, 18-21, 24, 27, 30-32, 35, 37, and 45 encompass SEQ ID NO: 6. SEQ ID NO: 6 was search and prior art was found. Examination was not extended to the remaining species.
Claims 3, 16-17, 36, 53-54, 62-63 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," 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 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) 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") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) 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 of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - This application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 - 1.825.
The sequences are SEQ ID NOs: 5-9. The deficiency is that the entry in the sequence listing for SEQ ID NOs: 5-9 is different that the structure in the claims and specification. See for example, claim 8:
PNG
media_image1.png
70
641
media_image1.png
Greyscale
The sequence listing omits the miscellaneous feature at position 1 in each of these sequences. It is also unclear whether the sequence should include a disulfide bond between the two cysteines given the definition of CNP on page 24, lines 18-24 of the specification.
Required response – Applicant must provide:
A "Sequence Listing" part of the disclosure, as described above in item 1); as well as
An amendment specifically directing entry of the "Sequence Listing" part of the disclosure into the application in accordance with 1.825(b)(2);
A statement that the "Sequence Listing" includes no new matter in accordance with 1.825(b)(5); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(b)(4).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, 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;
If the "Sequence Listing" part of the disclosure is submitted according to item 1) b), c), or d) above, Applicant must also provide:
A replacement CRF in accordance with 1.825(b)(6); and
Statement according to item 2) a) or b) above.
Claim Interpretation
BRI of the following claim terms is according to the definitions in the original specification:
therapeutically effective at p. 23, lines 12-27;
bolus at p. 23, lines 28-30;
a C-type natriuretic peptide or CNP at p. 24, lines 18-24;
a long acting CNP at p. 25, lines 8-25;
a very long acting CNP at p. 25, line 26 – p. 35, line 11;
a long acting CNP derivative at p. 26, line 12 – p. 27, line 6;
a very long acting CNP derivative at p. 27, line 7 – p. 28, line 2;
a NPRB agonist at p. 28, lines 7-15;
a long acting NPRB agonist at p. 28 lines 16-32;
a very long acting NPRB agonist at p. 29, lines 1-21;
treatment at p. 33, lines 28-29.
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
The claims are drawn to methods of treating a subject having a lung, liver, and/or kidney injury, or a system associated with a lung, liver, and/or kidney injury comprising administering a therapeutically effective bolus of a composition comprising a long acting CNP, a long acting CNP, a long acting CNP derivative, a long acting NPRB agonist, a very long acting CNP, a very long acting CNP derivative, a very longacting NPRB agonist, a long acting CNP agonist, a very long acting CNP agonist, or any combination thereof.
Scope of composition:
A “C-type natriuretic peptide” or “CNP” is defined at p. 24, lines 18-24: “a peptide including 22 amino acid residues, having a 17 amino acid residue ring structure formed by a disulfide bond, and an additional 5-amino acid residue extension at the N-terminal (GLSKGCFGLKLDRIGSMSGLGC [SEQ ID NO. 10]; where the letters are in accordance with conventional amino acid nomenclature, and the amino acid residues C-6 (at position 6) and C-22 (at position 22) are linked by a disulfide bond.”
A ”long acting CNP” is defined at p. 25, lines 8-25: “a CNP formulation that when administered as a single bolus dose to a mammalian subject (human, non-human, primate, dogs, rats, mice, etc.), the resulting elevation of CNP level in the plasma or elevation of plasma cyclic-GMP level above the baseline will be sustained for a duration of greater than 4 hours or greater than 6 hours depending on the species”. The CNP may or may not be covalently linked to a excipient or carrier such as a polymer, protein, sugar, detergent, and/or buffer.
A “very long acting CNP” is defined at p. 27, line 7 – p. 28, line 2: “a long-acting CNP formulation containing the 22 amino acid residue CNP formulated in such a way that when administered as a single bolus dose to subject, will have sustained presence in the plasma or sustained plasma cyclic-GMP elevation over the baseline of 24 hours or greater (e.g., up to 2-3 days or up to 1-4 weeks)”. The CNP may or may not be covalently linked to a excipient or carrier such as a polymer, protein, sugar, detergent, and/or buffer.
A “long acting CNP derivative” is defined at p. 26, line 12 – p. 27, line 6: “a CNP derivative that when administered as a single bolus dose to a mammalian subject or patient has sustained presence in the plasma or sustained plasma cyclic-GMP elevation over the baseline of greater than 4 hours, or greater than 6 hours, depending on the species.” The CNP derivative may be a modified CNP with at least 72% sequence identity to native CNP, may include the covalent addition of a chemical moiety, such as one or more additional amino acids and/or fatty acids and/or any chemical moiety and/or moieties at the N-terminal, C-terminal, or in the R-group of any amino acid residue in the CNP peptide, may include a substitution of 1 to 6 amino acid residues with different or unnatural amino acid residues, and may include deletion of 1 to 6 amino acid residues in a native CNP.
A “very long acting CNP derivative” is defined at p. 27, line 7 – p. 28, line 2: “a long acting CNP derivative or CNP derivative, that when administered as a single bolus dose to mammalian subject or patient, has sustained presence in the plasma or sustained plasma cyclic-GMP elevation over the baseline that has a duration of 24 hours or greater”. The CNP derivative may be a modified CNP with at least 72% sequence identity to native CNP, may include the covalent addition of a chemical moiety, such as one or more additional amino acids and/or fatty acids and/or any chemical moiety and/or moieties at the N-terminal, C-terminal, or in the R-group of any amino acid residue in the CNP peptide, may include a substitution of 1 to 6 amino acid residues with different or unnatural amino acid residues, and may include deletion of 1 to 6 amino acid residues in a native CNP. The CNP derivative may be combined with one or more excipient or carrier such as polymer, protein, sugar, detergent, or buffer.
A “NPRB agonist” is defined at p. 28, lines 7-15: “any compound, peptide or protein that does not contain the 22 amino acid residue CNP sequence in its structure and that can bind to NPRB, a cell catalytic receptor, and stimulate its intracellular guanylyl cyclase activity to increase intracellular or blood cyclic-GMP level, but with limited or no capability to bind and stimulate NPRA receptor”.
A “long acting NPRB agonist” is defined at p. 28 lines 16-32: “an NPRB agonist defined above, that, when administered as a single bolus dose to a mammalian subject or patient has sustained presence in the plasma or sustained plasma cyclic-GMP elevation over the baseline of greater than 4 hours or greater than 6 hours depending on the species.” The long acting NPRB agonist may or may not be covalently linked to excipient or carrier.
A ”a very long acting NPRB agonist” is defined at p. 29, lines 1-21: “a long NPRB agonist that, when administered as a single bolus dose to a mammalian subject or patient, will have sustained presence in the plasma or sustained plasma cyclic-GMP elevation over the baseline of 24 hours or greater”.
Only those sequences meeting the structural and functional requirements of the genus are encompassed by the claim. Therefore, claim 1, and dependent claims 20-21, 24, 27, and 30-31 encompasses all of the amino acid sequences and non-peptide structures meeting the structural and functional requirements above that are also able to:
not decrease blood pressure by more than 20% of a baseline blood pressure measurement taken prior to administration of the therapeutically effective bolus dose of the composition;
increase plasma cyclic-GMP level at from 1 hour to 12 hours after administration to above 1.5x of a baseline plasma cyclic-GMP level, wherein 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; and
treat the conditions and/or symptoms recited in parts (i)-(x) of the claim.
Claims 2, 4-8, and 18-19 partially limit the structure of the composition. These claims limit the structure of the long acting or very long acting CNP derivative but include the full, functionally-defined scope of all other composition of claim 1. Claim 32 partially limits the structure of the long acting or very long acting NPRB agonist to a polypeptide but includes the full, functionally-defined scope of all other composition of claim 1. Claims 35, 37, and 45 are the narrowest claims with respect to the composition but are still extremely broad, permitting a wide range of modifications to base peptide sequences. Even claim 37, which recites several species of long acting CNP derivatives, is unlimited with respect to the structure of very long acting CNP derivatives.
In addition, the specification states at page 25, lines 14-17, that the activity “is a result of CNP structure activity itself, or from the combination of the CNP with one or more components of a formulation containing the CNP”. As a result, it is not clear whether the structure of the composition is limited to the CNP itself or if it requires other unknown elements to achieve the claimed activity.
Scope of subject: In claims 1-2, 4-8, 18-20, 24, and 27, a subject having a lung, liver, and/or kidney injury, or a system associated with a lung, liver, and/or kidney injury includes i) acute lung injury (ALT), ii) acute respiratory distress syndrome (ARDS), iii) pulmonary edema, iv) elevated level of inflammatory cells in the lung, v) increased level or expression of inflammatory cytokines in the lung as compared to healthy lung, vi) increased protein level in lung alveolar space as compared to healthy lung, vii) low arterial blood oxygenation, wherein low arterial blood oxygenation is a blood PaO2 of below 60 mm Hg and/or a blood hemoglobin oxygen saturation (SpO2) of below 90%, viii) pneumonia, ix) fibrosis, x) kidney injury, and any combination thereof. The ALI or ARDS may be caused by: (i) a systemic insult selected from trauma, sepsis, bacteremia, pancreatitis, shock, multiple transfusions, disseminated intravascular coagulation, burns, drug overdose or toxicity, opioids, aspirin, phenothiazines, tricyclic antidepressant, amiodarone, chemotherapeutic agents, nitrofurantoin, protamine, thrombotic thrombocytopenia purpura, head injury, paraquat, and any combination thereof; or (ii) a pulmonary insult selected from aspiration of gastric content, lung intubation, embolism, tuberculosis, viral pneumonia, bacterial pneumonia, cytogenic organizing pneumonitis, airway obstruction, smoking free-base cocaine, near-drowning, toxic gas inhalation, oxygen toxicity, lung contusion, radiation exposure, high-altitude exposure, lung re-expansion, reperfusion, and any combination thereof. In claim 21, the subject has ALI or ARDS associated with pulmonary edema; low arterial blood oxygenation; elevated level of inflammatory cells in the lung; increase level or expression of inflammatory cytokine in the lung; sepsis; bacteremia; pneumonia, pulmonary fibrosis, or any combination thereof. In claims 35, 37, and 45, the subject has or is at risk of developing ALI or ARDS.
2) Actual reduction to practice/Working examples
The instant specification includes a limited reduction to practice: CNP-derivatives dCNP (SEQ ID NO: 6) and VLA-dCNP on LPS-induced acute lung injury (Examples 3-13); on Idiopathic Pulmonary Fibrosis (IPF) (Examples 14-15, 19); cisplatin (COOP) induced acute kidney injury (AKI) (Example 16, 18); dietinduced liver fibrosis (Example 17); and pharmacokinetics of bolus administration of dCNP (SEQ ID NO: 6), VLAdCNP, dCNP-s1 (SEQ ID NO:21) and dCNP-s2 (SEQ ID NO: 22). VLA-dCNP is a co-formulation of dCNP and a PK extending excipient described in detail on p. 74, line 18 – p. 74, line 4.
3) 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.
The specification at page 2 states that “ALI treatment remains elusive to the person of ordinary skill in the art.”
The specification at page 6 states that “increasing the bolus dose of a drug having CNP activity to increase drug exposure may be associated with unacceptable cardiovascular side-effects, such as hypotension.” There is a high level of unpredictability associated with maintaining or enhancing plasma levels of a CNP therapeutic agent while avoiding the dangerous cardiovascular side-effects.
4) Guidance in the specification/Structure-function correlation
The specification does not describe a general correlation between structure and function for the claimed genus. The role of each of the amino acids of CNP and NPRB on blood pressure, plasma cyclic-GMP levels, duration of action, and ability to treat lung, liver, and/or kidney injury or symptoms thereof, are not described. As a result, it is impossible to predict, based on the specification, how changing any position will affect the claimed function. In addition, it is not possible to predict how modifications to the peptide in the form of covalent attachment of polymers, aliphatics etc. affect blood pressure, plasma cyclic-GMP levels, duration of action, and ability to treat lung, liver, and/or kidney injury or symptoms thereof.
Claims 1-2, 4-8, 18-21, 24, 27, 30-32, 35, 37, and 45 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 LPS-induced acute lung injury (Examples 3-13), IPF (Examples 14-15, 19); COOP induced AKI (Example 16, 18), and dietinduced liver fibrosis. 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, and the treatment of lung, liver, and kidney injury 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 a method of treating LPS-induced acute lung injury, idiopathic pulmonary fibrosis, cisplatin-induced acute kidney injury, and diet induced liver fibrosis using dCNP (CH3(CH2)16C(=O)KKKKGGGGLSKGCFGLKLDRIGSMSGLGC (SEQ ID NO: 6)) and the co-formulation VLA-dCNP described in detail on p. 74, line 18 – p. 74, line 4, using a subcutaneous bolus dose meet the written description provision of 35 U.S.C. 112(a).
Claims 1-2, 4-8, 18-21, 24, 27, 30-32, 35, 37, and 45 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 LPS-induced acute lung injury, idiopathic pulmonary fibrosis, cisplatin-induced acute kidney injury, and diet induced liver fibrosis using dCNP (CH3(CH2)16C(=O)KKKKGGGGLSKGCFGLKLDRIGSMSGLGC (SEQ ID NO: 6)) and the co-formulation VLA-dCNP, comprising 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, using a subcutaneous bolus dose, does not reasonably provide enablement for the treatment of any other conditions with these compositions or the use of any other compositions or any other administration routes. 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 (2)-(8) are discussed above.
The scope of the claimed compositions (long acting CNP, a long acting CNP derivative, very long acting CNP, a very long acting CNP derivative etc) and therapeutic indications are extremely broad relative to the narrow reduction to practice in the specification. That fact combined with the level of unpredictability and complexity in the art, the relative skill in the art, and the lack of specific guidance in the specification, poses an undue burden of experimentation on one of ordinary skill in the art seeking to practice the claimed methods. The specification is an invitation to undertake a research program to identify additional compositions that could be used to carry out different embodiments of the claims. As such, the specification fails to meet the enablement provision of 35 U.S.C. 112(a).
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-2, 4-8, 18-21, 24, 27, 30-32, 35, 37, and 45 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The claims are indefinite because the structure of the elected species, which reads on each of these claims is ambiguous. SEQ ID NO: 6 is presented as a long acting CNP derivative in claims 8 and 37 as:
PNG
media_image1.png
70
641
media_image1.png
Greyscale
The definition of “CNP” on page 24, lines 18-24 of the specification states that a CNP has a 17 amino acid residue ring structure formed by a disulfide bond, and an additional 5 amino acid residue extension (Cys6 and Cys22 are linked by a disulfide bond). However, neither the claims nor the sequence listing require the disulfide bond. It is not clear whether the absence of the disulfide bond is an intentional modification of the CNP to a CNP derivative, or whether the disulfide is included based on the definition in the specification of CNP. Because of the alternative constructions, the structure of the long acting CNP derivative, even those that appear to be fully definite like SEQ ID NO: 6, are indefinite. The same issue exists for SEQ ID NOs: 5 and 7-9.
Claims 1-2, 4-8, 18-21, 24, 27, 30-32, 35, 37, and 45 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
In claim 1, the indefinite language is “a long acting CNP, a long acting CNP derivative, a long acting NPRB agonist, a very long acting CNP, a very long acting CNP derivative, a very long acting NPRB agonist, a long acting CNP agonist, a very long acting CNP agonist, or any combination thereof”.
The definitions on pages 25-27 of the specification state that “long-acting C-type natriuretic peptide” or “long acting CNP” refers to a CNP formulation that when administered as a single bolus dose to a mammalian subject (human, non-human, primate, dogs, rats, mice, etc.), the resulting elevation of CNP level in the plasma or elevation of plasma cyclic-GMP level above the baseline will be sustained for a duration of greater than 4 hours or greater than 6 hours depending on the species. A “very long-acting C-type natriuretic peptide” or “very long acting CNP” refers to a long-acting CNP formulation containing the 22 amino acid residue CNP formulated in such a way that when administered as a single bolus dose to subject, will have sustained presence in the plasma or sustained plasma cyclic-GMP elevation over the baseline of 24 hours or greater (e.g., up to 2-3 days or up to 1-4 weeks). The presence in the plasma means a detectable presence over and above the endogenous native agonist that are normally made by the subject or an analytical baseline level in the absence of administration of a therapeutic CNP formulation.
The language “a long acting CNP, a long acting CNP derivative, a long acting NPRB agonist, a very long acting CNP, a very long acting CNP derivative, a very long acting NPRB agonist, a long acting CNP agonist, a very long acting CNP agonist, or any combination thereof” is indefinite because the specification states at page 25, lines 14-17, that the activity “is a result of CNP structure activity itself, or from the combination of the CNP with one or more components of a formulation containing the CNP”. As a result, it is not clear whether the structure of the composition is limited to the CNP itself or if it requires other unknown elements to achieve the claimed activity. Even if it is possible to measure the duration of elevated CNP, it is not clear what structures are required to achieve the effect rendering the metes and bounds of the formulation indefinite.
In addition, the language is indefinite because it is not clear which duration (i.e. greater than four hours or greater than six hours) applies to which species. As a result, an ability to measure the duration of action is insufficient to determine whether or not a particular formulation meets the activity requirements of the claims.
The dependent claims fail to remedy these issues are likewise rejected.
Claims 1-2, 4-8, 18-21, 24, 27, and 30-32 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
In claim 1, the indefinite language is parts iv)-vii). The language is indefinite because it is not clear whether subjects who have symptoms iv)-vii) originating from conditions other than lung, liver, and/or kidney injury of i)-iii), vii), ix), and x) are included in the scope of the claim.
The dependent claims fail to remedy these issues are likewise rejected.
Claims 2, 4-7, 35, and 45 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 2, 4, 6-7, and 35, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claims 4, 6-7, and 35 the phrase "e.g." renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claims 4, 6, and 35 the phrase "preferably" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention.
Dependent claims 5 and 45 fail to remedy these issues and are likewise rejected.
Claims 18-19 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 18 recites the limitation "the polymer" in claim 1. There is insufficient antecedent basis for this limitation in the claim.
Claim 19 recites the limitation "Y" in claim 1. There is insufficient antecedent basis for this limitation in the claim.
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, 4-8, 18-21, 24, 27, 30-32, 35, 37, and 45 are rejected under 35 U.S.C. 103 as being unpatentable over Kimura et al. (Protective Effect of C-Type Natriuretic Peptide on Lipopolysaccharide-Induced Acute Lung Injury In Mice, Interactive CardioVascular and Thoracic Surgery, Volume 18, Issue suppl_1, June 2014, Page S53; hereafter “Kimura 2014”), and Kimura et al. (Protective effects of C-type natriuretic peptide on cisplatin-induced nephrotoxicity in Mice. Cancer Chemother Pharmacol 75, 1057–1063 (2015); hereafter “Kimura 2015”) 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.
Kimura 2014 teaches that C-type natriuretic peptide (CNP) had a protective effect on LPS-induced ALI mice accompanied by reducing the infiltration of inflammatory cells. CNP significantly attenuated the elevation of total cell counts and cytokine levels such as monocyte chemoattractant protein-1, tumour necrosis factor-alpha, interleukin-6, chemokine ligand 1, and macrophage inflammatory protein-2 in the BALF of mice after LPS injection. In addition, there were significantly fewer MPO-positive cells in the lung of CNP-treated mice than in control mice. Kimura 2014 teaches that CNP may be of value in prophylactic strategies for ALI following pulmonary resection surgery. See abstract.
Kimura 2015 teaches CNP inhibits nephrotoxicity and kidney cell damage induced by cisplatin. The mechanism of action may involve down-regulation of inflammatory cytokine expression in cisplatin-induced kidney injury and attenuation of apoptosis in renal tubular cells. CNP (2.5 μg/kg/min, subcutaneous reduced histological renal tubular damage and apoptosis induced by cisplatin and suppressed plasma blood urea nitrogen and creatinine levels, which were elevated by cisplatin administration. CNP treatment decreased the expression of kidney injury molecule-1 and monocyte chemoattractant protein-1, which were elevated in the kidney by cisplatin administration. CNP treatment attenuated the decrease in GC-B expression in cisplatin-induced kidney injury. See abstract.
Ascertaining the differences between the prior art and the claims at issue.
Neither Kimura 2014 not Kimura 2015 teach: 1) bolus administration, 2) that the CNP is a long-lasting or very long-lasting CNP, or 3) the precise effect of administration on cyclic-GMP levels, or blood pressure 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:
PNG
media_image2.png
741
627
media_image2.png
Greyscale
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 evidence of unexpected results.
It would have been obvious to one of ordinary skill in the art 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 CNP in the method of treating LPS-induced ALI taught by Kimura 2014 or for the CNP in the method of treating cisplatin-induced kidney injury taught by Kimura 2015. 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 references of Kimura 2014 and Kimura 2015 teach a method of which differs from the claimed method by the substitution of continuous administration of CNP 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 CNP (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 CNP that SEQ ID NO: 6 and 9 has this function in vivo and in fact has enhanced potency relative to hCNP-22. The CNP 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 treating LPS-induced ALI taught by Kimura 2014 and in the method of treating cisplatin-induced kidney injury taught by Kimura 2015. 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 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 and blood pressure in instant claim 1, 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 ALI or kidney injury by bolus administration for the reasons presented above. The effect on cyclic-GMP levels and blood pressure recited in the instant claim 1 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, claim 1 is obvious over the cited art.
Regarding claims 2, 4-8, 18-19, 30-32, 35, 37, and 45, 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 claim 20, Castillo et al. teach bolus administration via a subcutaneous route (p. 3, lines 16-23; Example 1; p. 35, lines 8-10).
Regarding claims 21, 24, and 27, the LPS-induced ALI taught by Kimura 2014 is a model for ALI associated with sepsis and infectious disease.
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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
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.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/CHRISTINA BRADLEY/Primary Examiner, Art Unit 1654