DETAILED ACTION
1. The present application is being examined under the pre-AIA first to invent provisions.
2. Claim filed on 12/15/2025 is acknowledged.
3. Claims 3, 5, 7, 9-14 and 16-34 have been cancelled.
4. Claims 1, 2, 4, 6, 8 and 15 are pending in this application.
5. Applicant elected with traverse of Group 1 (claims 1-6, 8-11 and 15) and SEQ ID NO: 1 as species of apelin; an oligomeric apelin as species of pegylated apelin molecule; myocardial infarction as species of disease or disorder associated with apelin; an activated PEG aldehyde linker as species of linker; and a cyanoborohydride as species of reducing agent in the reply filed on 12/5/2014. Since myocardial infarction as species of disease or disorder associated with apelin; an activated PEG aldehyde linker as species of linker; and a cyanoborohydride as species of reducing agent are not related to the elected Group 1, these elected species would not be searched and examined. Furthermore, the elected oligomeric apelin is a subgenus, not a species of pegylated apelin molecule, for example, the elected oligomeric apelin can be either a mono-pegylated apelin (claim 4) or di-pegylated apelin (claim 5). The Examiner telephoned Applicant’s representative, Mark S. Cohen, and left multiple messages on 12/29/2014 and 1/7/2015 for a specific species of pegylated apelin molecule. Applicant’s representative failed to respond to the Examiner’s telephone messages.
Restriction requirement was deemed proper and made FINAL in the previous office actions. The instant claims 1, 2, 4, 6, 8 and 15 are drawn to a pegylated apelin 36 molecule comprising one or more polyethylene glycol (PEG) molecules operably and specifically linked to at least one amino acid residue in the N-terminal of apelin 36, wherein said at least one amino acid residue is leucine, wherein said apelin 36 consists of amino acid residues 42-77 of SEQ ID NO: 1, and wherein said pegylated apelin 36 molecule comprises two or more monomers of apelin 36 that are operably linked to each other; and a pharmaceutical composition comprising a therapeutically effective amount of a pegylated apelin 36 that comprises one or more polyethylene glycol (PEG) molecules operably and specifically linked to at least one amino acid residue in the N-terminal of apelin 36, wherein said at least one amino acid residue is leucine, wherein said apelin 36 consists of amino acid residues 42-77 of SEQ ID NO: 1, and wherein said pegylated apelin 36 molecule comprises two or more monomers of apelin 36 that are operably linked to each other. A search was conducted on the elected species; and prior art was found. Claims 1, 2, 4, 6, 8 and 15 are examined on the merits in this office action.
Please note: SEQ ID NO: 1 as the elected species of apelin does not read on instant claims 1, 2, 4, 6, 8 and 15.
Maintained Rejections
Claim Rejections - 35 U.S.C. § 103
6. The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
7. The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
8. Claims 1, 2, 4, 6, 8 and 15 remain rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Krieg (US 2004/0219152 A1, filed with IDS) in view of Veronese et al (DDT, 2005, 10, pages 1451-1458, cited and enclosed in the previous office actions) and Mammen et al (Angew. Chem. Int. Ed., 1998, 37, pages 2754-2794, cited and enclosed in the previous office actions), and as evidenced by Berry et al (Circulation, 2004, 110, pages II-187-II-193, filed with IDS).
The instant claims 1, 2, 4, 6, 8 and 15 are drawn to a pegylated apelin 36 molecule comprising one or more polyethylene glycol (PEG) molecules operably and specifically linked to at least one amino acid residue in the N-terminal of apelin 36, wherein said at least one amino acid residue is leucine, wherein said apelin 36 consists of amino acid residues 42-77 of SEQ ID NO: 1, and wherein said pegylated apelin 36 molecule comprises two or more monomers of apelin 36 that are operably linked to each other; and a pharmaceutical composition comprising a therapeutically effective amount of a pegylated apelin 36 that comprises one or more polyethylene glycol (PEG) molecules operably and specifically linked to at least one amino acid residue in the N-terminal of apelin 36, wherein said at least one amino acid residue is leucine, wherein said apelin 36 consists of amino acid residues 42-77 of SEQ ID NO: 1, and wherein said pegylated apelin 36 molecule comprises two or more monomers of apelin 36 that are operably linked to each other.
Krieg, throughout the patent, teaches a composition comprising apelin peptide as a therapeutical agent for promoting angiogenesis; and methods of promoting angiogenesis in a patient that has a disease or condition that is indicated by decreased vascularization with such composition, for example, page 1, paragraphs [0003] and [0009]; page 2, paragraph [0011]; and claims 33, 36-38 and 43-50. Krieg further teaches apelin peptides of SEQ ID NOs: 1 and 2 are preferred, for example, page 2, paragraph [0011]; page 4, paragraph [0036]; page 15, paragraph [0134]; and claims 36-38 and 43. Apelin peptide of SEQ ID NO: 1 in Krieg is identical to apelin of instant SEQ ID NO: 1; and it reads on instant SEQ ID NO: 1 as the elected species of apelin. Apelin peptide of SEQ ID NO: 2 in Krieg is identical to apelin 36 consisting of amino acids 42-77 of instant SEQ ID NO: 1 with Leu as the first N–terminal amino acid; and it meets the limitation of apelin 36 recited in instant claims 1, 2, 4 and 15. Krieg also teaches fusion protein comprising non-apelin peptide fused to the N-terminus of the apelin peptide, including a GST-apelin fusion wherein GST is fused to the N-terminus of apelin, or a fusion protein comprising a heterologous signal sequence at the N-terminus of the apelin peptide, for example, page 5, paragraph [0041]. Furthermore, Krieg teaches the C-terminal 13 amino acids of the apelin polypeptide is necessary and sufficient for the ability of an apelin polypeptide to interact with APJ, for example, page 1, paragraph [0006]. Therefore, in view of the teachings of Krieg as a whole, one of ordinary skilled in the art would understand and reasonably expect that modification at the N-terminus of apelin 36 is tolerable and less likely to affect its functionality.
The difference between the reference and instant claims 1, 2, 4, 6, 8 and 15 is that the reference does not explicitly teach apelin 36 is covalently and specifically conjugated to PEG and comprises two or more monomers of apelin 36 that are operably linked to each other; the type of PEGylation recited in instant claims 1, 4, 6, 8 and 15; and an oligomeric apelin as the elected species of pegylated apelin molecule.
However, Veronese et al, throughout the literature, teach PEGylation defines the modification of a protein, peptide or non-peptide molecule by the linking of one or more polyethylene glycol (PEG) chains; the advantages of PEGylation of peptide drugs wherein the PEG molecule is covalently attached to the peptide, such as a prolonged residence in body, a decreased degradation by metabolic enzymes and a reduction or elimination of protein immunogenicity; and PEGylation plays an important role in drug delivery, enhancing the potentials of peptides and proteins as therapeutic agents, for example, Abstract; page 1452, Figure 1; and page 1455, Section “Improved protein drugs by PEGylation”. Veronese et al further teach amino group modification, including the N-terminal α-amino group, with PEG molecule is the most common modification and often the first approach in new PEG-protein/peptide projects, for example, pages 1452-1453, Section “Amino group modification”. Veronese et al also teach site-specific amino PEGylation, including site-specific PEGylation of the N-terminal α-amino group; the method to prepare site-specific PEGylation of the N-terminal α-amino group; and the advantages of site-specific PEGylation, such as helping the purification and the characterization procedures since mixtures of PEGylated products are avoided and site-specific modification leads to a better preservation of the native protein activity in the conjugate, for example, page 1452, right column, the last paragraph in Section “Amino group modification”. Furthermore, Veronese et al teach approved PEG conjugates with PEG of 5 kDa, 12 KDa, 20 kDa and 40 KDa; and mono-conjugated peptide drug, for example, page 1455, Table 4 and Section “Improved protein drugs by PEGylation”. In addition, Veronese et al teach the PEG molecule is covalently attached to the peptide either directly or via a linker, for example, pages 1452-1453, Section “Amino group modification”; and page 1453, Table 2. Therefore, in view of the combined teachings of Krieg and Veronese et al, it would have been obvious to one of ordinary skilled in the art to develop a mono-conjugated apelin 36 molecule with PEG of 5 kDa, 12 KDa, 20 kDa or 40 KDa covalently and specifically attached to the N-terminal α-amino group of leucine residue of apelin 36, either directly or via a linker, wherein the apelin 36 molecule consists of amino acids 42-77 of instant SEQ ID NO: 1.
Furthermore, Mammen et al, throughout the literature, teach polyvalent interaction; and design of pharmaceutical agents based on polyvalence, for example, Abstract. Mammen et al further teach the advantages of polyvalent interaction in biological systems, including enhanced affinity, increasing strength and specificity of binding, preventing undesirable interaction, and many others, for example, page 2767, Figure 9; and pages 2771-2774, Section “4.1. Functional advantages of Polyvalent Interactions”.
Therefore, it would have been obvious to one of ordinary skilled in the art to combine the teachings of Krieg, Veronese et al and Mammen et al to develop an oligomeric apelin with PEG covalently and specifically attached to the N-terminal α-amino group of leucine residue of apelin 36 as a therapeutical agent for promoting angiogenesis, wherein said apelin 36 consists of amino acids 42-77 of instant SEQ ID NO: 1, and wherein said oligomeric pegylated apelin 36 comprises two or more monomers of apelin 36 that are operably linked to each other; and a pharmaceutical composition comprising a therapeutically effective amount of such oligomeric apelin with PEG covalently and specifically attached to the N-terminal α-amino group of leucine residue of apelin 36. It reads on an oligomeric apelin as the elected species of pegylated apelin molecule.
With regards to the limitation recited in instant claim 2, in the instant case, Veronese et al explicitly teach the advantages of PEGylation of peptide drugs include a prolonged residence in body, a decreased degradation by metabolic enzymes and so on. Mammen et al explicitly teach the advantages of polyvalent interaction in biological systems. Therefore, one of ordinary skilled in the art would understand and reasonably expect the oligomeric apelin (a peptide) with PEG covalently and specifically attached to the N-terminal α-amino group of leucine residue of apelin 36 developed from the combined teachings of Krieg, Veronese et al and Mammen et al would have a prolonged circulating life, relative to a non-pegylated apelin 36. Furthermore, as evidenced by Berry et al, one of the bioactivities of apelin is inotropic effects on heart through the apelin-APJ signaling pathway (see Title of Berry et al). Since the oligomeric apelin with PEG covalently and specifically attached to the N-terminal α-amino group of leucine residue of apelin 36 developed from the combined teachings of Krieg, Veronese et al and Mammen et al would have a prolonged residence in body and a decreased degradation by metabolic enzymes, one of ordinary skilled in the art would understand and reasonably expect the oligomeric apelin with PEG covalently and specifically attached to the N-terminal α-amino group of leucine residue of apelin 36 developed from the combined teachings of Krieg, Veronese et al and Mammen et al would have an extended inotropic effects, relative to a non-pegylated apelin 36. In addition, since the oligomeric apelin with PEG covalently and specifically attached to the N-terminal α-amino group of leucine residue of apelin 36 developed from the combined teachings of Krieg, Veronese et al and Mammen et al meets all the structural limitations of the pegylated apelin 36 molecule recited in instant claim 1, the oligomeric apelin with PEG covalently and specifically attached to the N-terminal α-amino group of leucine residue of apelin 36 developed from the combined teachings of Krieg, Veronese et al and Mammen et al would necessarily have the same properties and functionality of the pegylated apelin 36 molecule recited in instant claim 1. Therefore, the oligomeric apelin with PEG covalently and specifically attached to the N-terminal α-amino group of leucine residue of apelin 36 developed from the combined teachings of Krieg, Veronese et al and Mammen et al would exhibit a prolonged circulating life and an extended inotropic effect, relative to a non-pegylated apelin 36. And, the MPEP states: “Products of identical chemical composition cannot have mutually exclusive properties.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990) (see MPEP § 2112.01 II).
One of ordinary skilled in the art would have been motivated to combine the teachings of Krieg, Veronese et al and Mammen et al to develop an oligomeric apelin with PEG covalently and specifically attached to the N-terminal α-amino group of leucine residue of apelin 36 as a therapeutical agent for promoting angiogenesis, wherein said apelin 36 consists of amino acids 42-77 of instant SEQ ID NO: 1, and wherein said oligomeric pegylated apelin 36 comprises two or more monomers of apelin 36 that are operably linked to each other; and a pharmaceutical composition comprising a therapeutically effective amount of such oligomeric apelin with PEG covalently and specifically attached to the N-terminal α-amino group of leucine residue of apelin 36, because Veronese et al teach the advantages of PEGylation of peptide drugs wherein the PEG molecule is covalently attached to the peptide. Veronese et al further teach amino group modification, including the N-terminal α-amino group, with PEG molecule is the most common modification and often the first approach in new PEG-protein/peptide projects. Veronese et al also teach site-specific amino PEGylation, including site-specific PEGylation of the N-terminal α-amino group; the method to prepare site-specific PEGylation of the N-terminal α-amino group; and the advantages of site-specific PEGylation. And as stated above, in view of the teachings of Krieg as a whole, one of skill in the art would understand and reasonably expect that modification at the N-terminus of apelin 36 is tolerable and less likely to affect its functionality. Therefore, in view of the combined teachings of Krieg and Veronese et al, it would have been obvious to one of ordinary skilled in the art to develop a mono-conjugated apelin 36 molecule with PEG covalently and specifically attached to the N-terminal α-amino group of leucine residue of apelin 36, either directly or via a linker, wherein the apelin 36 molecule consists of amino acids 42-77 of instant SEQ ID NO: 1. Furthermore, Mammen et al, throughout the literature, teach polyvalent interaction; and design of pharmaceutical agents based on polyvalence. Mammen et al further teach the advantages of polyvalent interaction in biological systems, including enhanced affinity, increasing strength and specificity of binding, preventing undesirable interaction, and many others.
A person of ordinary skilled in the art would have reasonable expectation of success in combining the teachings of Krieg, Veronese et al and Mammen et al to develop an oligomeric apelin with PEG covalently and specifically attached to the N-terminal α-amino group of leucine residue of apelin 36 as a therapeutical agent for promoting angiogenesis, wherein said apelin 36 consists of amino acids 42-77 of instant SEQ ID NO: 1, and wherein said oligomeric pegylated apelin 36 comprises two or more monomers of apelin 36 that are operably linked to each other; and a pharmaceutical composition comprising a therapeutically effective amount of such oligomeric apelin with PEG covalently and specifically attached to the N-terminal α-amino group of leucine residue of apelin 36.
Response to Applicant's Arguments
9. Applicant argues that “Veronese teaches that it is well-known in the art that PEGylation of proteins is often accompanied by loss of biological activity, and a precise chemical investigation of the conjugate structure is required to verify the advantages of PEGylation. Together with the complex relationship between structure and function of a polypeptide generally acknowledged in the art, the functional effects of modifying or PEGylation of a protein or peptide cannot be determined on a theoretical basis.”; and “In view of the above remarks, Applicants submit that the combination of the cited references does not teach or suggest each and every aspect of the present claims. The claims presented herein are not obvious in view of the cited references. Accordingly, Applicants respectfully request withdrawal of the rejection.”
10. Applicant's arguments have been fully considered but have not been found persuasive.
In the instant case, the Examiner would like to point out that instant claims 1, 2, 4, 6, 8 and 15 are rejected under pre-AIA 35 U.S.C. 103(a) (obviousness type), and the rejection is based on the combined teachings of Krieg, Veronese et al and Mammen et al; therefore, it is not necessary for each of the cited references to teach all the limitations of instant claims. Furthermore, the Examiner would like to point out that the MPEP states "One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references…" (see MPEP § 2145 IV).
In response to Applicant's arguments about instant rejection: The Examiner understands that the effect of PEGylation on a peptide/protein is not absolutely predictable. However, in the instant case, as repeatedly stated in the previous office actions:
First, the Examiner would like to point out that Krieg explicitly teaches “The peptide consisting of the C-terminal 13 amino acids of the apelin polypeptide is necessary and sufficient for the ability of an apelin polypeptide to interact with APJ.” (see page 1, paragraph [0006]; and Figures 1 and 2). And as stated in Section 8 above, in the instant case, in view of the teachings of Krieg as a whole, one of ordinary skilled in the art would understand and reasonably expect that modification at the N-terminus of apelin 36 is tolerable and less likely to affect its functionality.
Second, as stated previously, it appears to the Examiner that Applicant agrees with the Examiner that apelin 13 is the receptor binding site of apelin 36 by citing the Ma et al reference (see Applicant’s Arguments/Remarks filed on 4/29/2021). Apelin 13 consists of the C-terminal 13 amino acids of the apelin polypeptide with the amino acid sequence LVQPRGSRNGPGPWQGGRRKFRRQRPRLSHKGPMPF taught in Krieg.
Third, with regards to PEGylation of peptide/protein drugs, it is well known in the PEGylation art that pegylation can influence the binding affinity of therapeutic proteins to cellular receptors; and it is crucial that the PEG is attached at a site distant from the binding site (see page 215, right column, the 1st paragraph; and page 216, right column, the 1st paragraph in Harris et al, Nature Reviews, 2003, 2, pages 214-221, cited and enclosed in the previous office actions). And as stated above, Krieg explicitly teaches “The peptide consisting of the C-terminal 13 amino acids of the apelin polypeptide is necessary and sufficient for the ability of an apelin polypeptide to interact with APJ.” (see page 1, paragraph [0006]; and Figures 1 and 2). Therefore, in the instant case, in view of the teachings of Krieg as a whole, one of ordinary skilled in the art would understand and reasonably expect that modification at the N-terminus of apelin 36 is tolerable and less likely to affect its functionality.
Fourth, as stated in the previous office actions, pegylation of proteins and/or peptides has been extensively and successful applied to various peptides/proteins since 1970s, as disclosed in Veronese et al, Harris et al (Nature Reviews, 2003, 2, pages 214-221, cited and enclosed in the previous office actions) and many others. In the instant case, Applicant fails to provide any reasoning why apelin 36 is not able to be modifier by PEG. Therefore, Applicant is suggested to provide evidence that due to certain properties of apelin 36, apelin 36 is not able to be modified by PEG; and Applicant is able to modify apelin 36 due to whatever that is not normally known in the field of pegylation.
Fifth, with regards to Applicant's arguments about absent experimental data showing the functional effects of modifying the instant claimed peptide with PEG, the Examiner would like to point out that instant claims are rejected under pre-AIA 35 U.S.C. 103(a); and providing experimental data to show the functional effects of modifying the instant claimed peptide with PEG is impossible to achieve for a rejection set forth under pre-AIA 35 U.S.C. 103(a) (obviousness type). Otherwise, the instant claims would be rejected under pre-AIA 35 U.S.C. 102.
Taken all these together, considering the state of art regarding PEGylation of protein/peptide drugs as discussed in Veronese et al, Harris et al (Nature Reviews, 2003, 2, pages 214-221, cited and enclosed in the previous office actions) and many others, and in view of the teachings of Krieg, one of ordinary skilled in the art would understand and reasonably expect that attaching PEG at the N-terminus of apelin 36 (a site distant from the binding site) would not have any adverse effects on its functionality. And considering the state of art regarding PEGylation of protein/peptide drugs as discussed in Veronese et al, Harris et al (Nature Reviews, 2003, 2, pages 214-221, cited and enclosed in the previous office actions) and many others, and in view of the combined teachings of the cited prior art references as set forth in Section 8 above, it would have been obvious to one of ordinary skilled in the art and/or a person of ordinary skilled in the art would have reasonable expectation of success in developing the pegylated apelin 36 molecule recited in instant claims 1, 2, 4, 6, 8 and 15.
And as repeatedly stated in the previous office actions, other than statements/arguments, Applicant fails to provide any reasoning why apelin 36 is not able to be modified by PEG. Therefore, Applicant is suggested to provide evidence that due to certain properties of apelin 36, apelin 36 is not able to be modified by PEG; and Applicant is able to modify apelin 36 due to whatever that is not normally known in the field of pegylation.
In addition, with regards to the expectation of success, the MPEP states: “Absolute predictability is not a necessary prerequisite to a case of obviousness. Rather, a degree of predictability that one of ordinary skill would have found to be reasonable is sufficient. The Federal Circuit concluded that “[g]ood science and useful contributions do not necessarily result in patentability.” Id. at 1364, 83 USPQ2d at 1304.” (see MPEP § 2145).
Furthermore, in the instant case, the combined teachings of Krieg, Veronese et al and Mammen et al as set forth in Section 8 above teach each and every limitation recited in instant claims 1, 2, 4, 6, 8 and 15. And other than statements/arguments, Applicant fails to point out how and/or why the combination of the cited references does not teach or suggest each and every aspect of the present claims. Further clarification is required.
Taken all these together, the rejection is deemed proper and is hereby maintained.
The Harris et al reference is cited only for the purpose of rebutting Applicant's arguments, therefore, it is not cited as a prior art reference.
Conclusion
THIS ACTION IS MADE FINAL. 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.
No claim is allowed.
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/LI N KOMATSU/Primary Examiner, Art Unit 1658
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