A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 7/13/2026 has been entered.
DETAILED ACTION
1. The present application is being examined under the pre-AIA first to invent provisions.
2. Claim filed on 7/13/2026 is acknowledged.
3. Claims 3-5, 7, 9-14 and 16-34 have been cancelled.
4. Claims 1, 2, 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, 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 wherein said pegylated apelin 36 is a mono-pegylated apelin 36; 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, 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, 6, 8 and 15.
New Objections
6. Claim 1 is objected to for the following minor informality: Applicant is suggested to amend claim 1 as “…wherein said apelin 36 consists of amino acid residues 42-77 of SEQ ID NO: 1, wherein said pegylated apelin 36 molecule comprises two or more monomers of apelin 36 that are operably linked to each other, and wherein…”.
New Rejections
Claim Rejections - 35 U.S.C. § 112 second paragraph
7. 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.
8. Claims 1, 2, 6 and 8 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 pre-AIA the applicant regards as the invention.
9. Claim 1 recites “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 wherein said pegylated apelin 36 is a mono-pegylated apelin 36”. With regards to the term “mono-pegylated”, the instant specification fails to define it. Therefore, in the instant case, the term “mono-pegylated” is interpretated as what is generally accepted in the Pegylation art, in that mono-pegylated refers to a biochemical modification process in which exactly one polyethylene glycol (PEG) polymer chain is covalently attached to a bioactive molecule. Thus, it is unclear how the recited “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” can be a mono-pegylated apelin 36. Therefore, the metes and bounds of instant claim 1 is vague and indefinite. Because claims 2, 6 and 8 depend from indefinite claim 1, and none of the dependent claims clarifies the point of confusion, they must also be rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph.
Furthermore, for the purpose of this examination and in the broadest reasonable interpretation, the Examiner is interpretating instant claim 1 as “A pegylated apelin 36 molecule comprising polyethylene glycol (PEG) molecule operably and specifically linked to leucine at the N-terminus of apelin 36, 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 wherein each of the apelin 36 monomer is mono-pegylated”. Such interpretation applies to all the rejections set forth below.
In addition, Applicant is suggested to amend claim 1 accordingly to overcome instant rejection.
Maintained/Revised Rejections
Claim Rejections - 35 U.S.C. § 103
10. 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.
11. 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.
12. (Revised due to Applicant’s amendment to the claim) Claims 1, 2, 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, 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 wherein said pegylated apelin 36 is a mono-pegylated apelin 36; 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 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, 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, 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 one PEG molecule 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 such pegylated apelin 36 that are operably linked to each other; and a pharmaceutical composition comprising a therapeutically effective amount of such oligomeric apelin. 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) developed from the combined teachings of Krieg, Veronese et al and Mammen et al above 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 developed from the combined teachings of Krieg, Veronese et al and Mammen et al above 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 developed from the combined teachings of Krieg, Veronese et al and Mammen et al above would have an extended inotropic effects, relative to a non-pegylated apelin 36. In addition, since the oligomeric apelin developed from the combined teachings of Krieg, Veronese et al and Mammen et al above meets all the structural limitations of the pegylated apelin 36 molecule recited in instant claim 1, the oligomeric apelin developed from the combined teachings of Krieg, Veronese et al and Mammen et al above would necessarily have the same properties and functionality of the pegylated apelin 36 molecule recited in instant claim 1. Therefore, the oligomeric apelin developed from the combined teachings of Krieg, Veronese et al and Mammen et al above 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 one PEG molecule 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 such pegylated apelin 36 that are operably linked to each other; and a pharmaceutical composition comprising a therapeutically effective amount of such oligomeric apelin, 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 one PEG molecule 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 one PEG molecule 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 such pegylated apelin 36 that are operably linked to each other; and a pharmaceutical composition comprising a therapeutically effective amount of such oligomeric apelin.
Response to Applicant's Arguments
13. Applicant argues that “A skilled artisan would not have a reasonable expectation of success (absent hindsight) for a mono-pegylated apelin-36 at the N-terminus of that apelin-36.”; and “The Examiner has not addressed the disadvantages of pegylation disclosed in Veronese. Neither has the Examiner shown why it would be obvious to one of ordinary skill in the art to arrive at the claimed invention when Veronese is taken as a whole, including the disadvantages of pegylation discussed in Veronese.”
14. 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, 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 that “A skilled artisan would not have a reasonable expectation of success (absent hindsight) for a mono-pegylated apelin-36 at the N-terminus of that apelin-36.”:
First, as repeatedly stated in the previous office actions, 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 12 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 in Section 12 above, Krieg explicitly 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. Furthermore, 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 LVQPRGSRNGPGPWQ GGRRKFRRQRPRLSHKGPMPF taught in Krieg. And in the instant case, the two Lys residues are either in the receptor binding site of apelin 36 or very close to the receptor binding site of apelin 35.
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).
Taken all these together, 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. Furthermore, in view of the well-known receptor binding site of apelin 36 and what is well known in the art of PEGylation of peptide/protein drugs, in particular it is crucial that the PEG is attached at a site distant from the binding site, one of ordinary skilled in the art would understand and reasonably expect that attaching PEG to the N-terminal α-amino group of leucine residue of apelin 36 would less likely affect its ability to bind to the APJ receptor, while attaching PEG to the two Lys residues that are either in the receptor binding site of apelin 36 or very close to the receptor binding site of apelin 36 would significantly affect its ability to bind to the APJ receptor. And in the instant case, the data provided by Applicant further confirm what is well known in the art regarding both the receptor binding site of apelin 36 and the proper site for PEGylation of a known protein/peptide.
In addition, with regards to Applicant’s arguments about hindsight bias, in the instant case, Applicant fails to point to any facet of instant rejection that is not found in the cited prior art references and/or what is well known in the art regarding PEGylation of protein/peptide drugs. It is unclear to the Examiner which part of the instant rejection is not based on the combined teachings of the cited references. Merely pointing out the differences between each of the cited references and instant claimed invention is not proof of hindsight reasoning. And, the MPEP states “"[a]ny judgment on obviousness is in a sense necessarily a reconstruction based on hindsight reasoning, but so long as it takes into account only knowledge which was within the level of ordinary skill in the art at the time the claimed invention was made and does not include knowledge gleaned only from applicant’s disclosure, such a reconstruction is proper." In re McLaughlin, 443 F.2d 1392, 1395, 170 USPQ 209, 212 (CCPA 1971).” (see MPEP § 2145).
In response to Applicant’s arguments that “The Examiner has not addressed the disadvantages of pegylation disclosed in Veronese. Neither has the Examiner shown why it would be obvious to one of ordinary skill in the art to arrive at the claimed invention when Veronese is taken as a whole, including the disadvantages of pegylation discussed in Veronese.”:
First, the Examiner would like to point out that Applicant fails to provide the Zhang et al reference cited in Applicant’s Arguments/Remarks filed on 7/13/2026. Since it is impossible for the Examiner to consider such reference as a whole, Applicant’s arguments based on one particular section of such reference are moot.
Second, as repeatedly 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. The Examiner understands that there are both advantages and disadvantages of PEGylation of proteins and/or peptides. However, in the instant case, 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, one of ordinary skilled in the art would understand and reasonably expect the advantages of PEGylation of proteins and/or peptides overweight the disadvantages of PEGylation of proteins and/or peptides.
Furthermore, it appears to the Examiner that Applicant firmly believes that one of ordinary skilled in the art would only attaching PEG to any protein and/or peptide if there is no disadvantage of Pegylation on such protein and/or peptide; and/or the disadvantages of PEGylation of proteins and/or peptide overweight the advantages of PEGylation of proteins and/or peptides. However, considering PEGylation of proteins and/or peptides has been extensively and successful applied to various peptides/proteins since 1970s, it is unclear to the Examiner on what Applicant’s belief is based. Further clarification is required.
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 12 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, 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 with one PEG molecule covalently and specifically attached to the N-terminal α-amino group of leucine residue of apelin 36. Therefore, Applicant is suggested to provide evidence that due to certain properties of apelin 36, apelin 36 is not able to be modified with one PEG molecule covalently and specifically attached to the N-terminal α-amino group of leucine residue of apelin 36; and Applicant is able to modify apelin 36 by covalently and specifically attaching one PEG molecule to the N-terminal α-amino group of leucine residue of 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).
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
No claim is allowed.
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/LI N KOMATSU/Primary Examiner, Art Unit 1658
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