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 .
Status of the Claims
Claims 1, 6 – 12 and 16 – 20 were pending. Claims 1, 6 – 8, 11 – 12 and 18 – 19 have been amended. Claims 1, 6 – 12 and 16 – 20 are currently pending and are the subject of this Office Action.
OBJECTIONS WITHDRAWN
Claim Objections
Claim 1 was objected to because of informalities.
In view of the amendment to claim 1 in the reply of 04/09/2026, this objection is withdrawn.
REJECTION MAINTAINED IN MODIFIED FORM
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 1, 6 – 12 and 16 – 20 are rejected under 35 U.S.C. 103 as being unpatentable over ARMSTRONG (US 2017/327560 A1, published 11/16/2017, an IDS reference) in view of SERMADIRAS (WO 2016/131893 A1, published 08/25/2016; on IDS submitted 04/11/2024).
According to the present specification, a deletion variant in which 14 amino acids at positions 1 to 14 of the amino acid sequence of SEQ ID NO: 1 is deleted has the sequence of SEQ ID NO: 2 (p. 16, second paragraph, last sentence).
ARMSTRONG is directed to fusion proteins containing a half-life extension protein, a linker, and a GDF15 protein and methods of using the fusion proteins for treating or metabolic preventing diseases, disorders or conditions. See abstract. ARMSTRONG teaches that the fusion protein comprises: (a) a half-life extension protein, (b) a linker, and (c) a GDF15 protein, wherein the fusion protein is arranged from N-terminus to C-terminus in the order (a)-(b)-(c). See ARMSTRONG at claim 1. ARMSTRONG discloses an Fc-fusion of GDF15 (see paragraph [0004]) and teaches that the constant fragment domain (Fc) of an immunoglobulin (Ig) is known to extend the half-life of proteins to which it is fused (see paragraph 0074). ARMSTRONG also teaches a linker comprising the sequence (GGGGS)n, where n is 2 to 20. See paragraph 0108.
ARMSTRONG teaches a dimer comprising two polypeptide chains, wherein each chain comprises from N-terminus to C-terminus an HSA region, a linker, and a GDF15 region. See ARMSTRONG at claim 27. Furthermore, ARMSTRONG teaches that GDF15, a member of the TGFβ family, is a secreted protein that circulates in plasma as a 25 kDa homodimer (see ARMSTRONG at paragraph 0002). Thus, it would have been obvious that the fusion protein dimerizes between GDF15s of the fusion polypeptide dimer.
Thus, ARMSTRONG teaches the fusion polypeptide dimer comprising two fusion polypeptides, each fusion polypeptide comprising: GDF15 (Growth/differentiation factor 15) or a functional variant of GDF15, and Fc region of an immunoglobulin of present claims 1, 7 and 12.
However, ARMSTRONG does not expressly indicate that the Fc region of fusion protein is a single chain of human IgG4 Fc region of SEQ ID NO: 7.
SERMADIRAS is directed to GIP/GLP- 1 dual agonist polypeptides, fusion proteins, and synthetic and conjugated proteins for the treatment of hypoglycemic conditions, e.g., type-2 diabetes. See abstract. SERMADIRAS teaches a fusion polypeptide with a human IgG4 Fc region of SEQ ID NO: 7. See paragraphs 0235 and 0237 and Appendix. Furthermore SERMADIRAS teaches a linker that comprises (GGGGS)n, wherein n is 1, 2, 3, 4, 5, 6, 7, or 8. See paragraph 0238.
Because ARMSTRONG discloses an Fc-fusion of GDF15 that demonstrates an increased solubility/stability (see paragraph 0007) and is effective in treating metabolic conditions and SERMADIRAS teaches a fusion polypeptide with a human IgG4 Fc region of SEQ ID NO: 7 effective in treating metabolic conditions, it would have been obvious to one having ordinary skill in the art to modify ARMSTRONG’s GDF15 fusion polypeptide with SERMADIRAS’s IgG4 Fc region to arrive at the compositions of claims 1 and 7 and the method of enhancing in vivo stability of GDF15 of claim 12.
Regarding claims 6 and 17, while neither ARMSTRONG nor SERMADIRAS expressly state that the disclosed fusion polypeptides have at least 1.5 times increased in vivo half-life compared to GDF15 or its functional variant which is not linked to Fc region of the immunoglobulin, the cited references attribute the stability of the fusion polypeptide to the Fc region (discussed above). Thus, ARMSTRONG in view of SERMADIRAS renders the increased in vivo half-life of the fusion proteins obvious, and the fusion polypeptide rendered obvious by ARMSTRONG in view of SERMADIRAS would inherently achieve at least 1.5 times increased in vivo half-life compared to GDF15 or its functional variant which is not linked to Fc region of the immunoglobulin.
Regarding claims 8 – 10, ARMSTRONG discloses nucleic acids and expression vectors encoding the fusion proteins. See paragraph 0001. ARMSTRONG further discloses expression vector comprising a nucleic acid molecule encoding the fusion protein or a recombinant host cell comprising a nucleic acid molecule encoding the fusion protein. See paragraphs 0014 and 0015.
Regarding claim 11, ARMSTRONG discloses a method of obtaining a fusion protein by (1) culturing a host cell comprising a nucleic acid molecule encoding the fusion protein under a condition that the fusion protein is produced, and (2) recovering the fusion protein produced by the host cell. See paragraph [0016].
Regarding claim 16, ARMSTRONG discloses the sequence of SEQ ID NO: 2. ARMSTRONG’s SEQ ID NO: 11 is identical to present SEQ ID NO: 2. See Appendix.
Regarding claim 18, ARMSTRONG discloses fusion proteins FP1s as intact dimers in serum (see paragraphs 0026 and 0037), discloses nucleic acids and expression vectors encoding the fusion proteins (see paragraph 0001), discloses expression vector comprising a nucleic acid molecule encoding the fusion protein or a recombinant host cell comprising a nucleic acid molecule encoding the fusion protein (see paragraphs 0014 and 0015). Thus, ARMSTRONG renders claim 18 obvious.
Regarding claim 19, ARMSTRONG discloses a method of reducing body weight via administration of the FP1 fusion protein. See Example 10, paragraphs 0159 – 0172.
Regarding claim 20, ARMSTRONG discloses a method of treating a metabolic disorder selected from the group consisting of type 2 diabetes, elevated glucose levels, elevated insulin levels, obesity, . . . See paragraph 0021.
Response to Arguments
On p. 7, above the last paragraph, of the reply of 04/09/2026, Applicant argues that “[t]here would not have been motivation to select IgG4 Fc (SEQ ID NO: 7) from Sermadiras and combine Sermadiras with Armstrong as alleged in the Office Action” and provides reasons why “[t]here would not have been motivation to select IgG4 Fc (SEQ ID NO: 7) from Sermadiras and combine Sermadiras with Armstrong as alleged in the Office Action” (p. 7, last paragraph – p. 8, first paragraph).
Applicant’s argument has been fully considered but not found persuasive because SERMADIRAS is concerned with improving metabolic stability of peptides and teaches that the “GIP/GLP- 1 agonist polypeptide, can comprise a recombinant fusion polypeptide or a synthetic conjugated polypeptide comprising one or more additional components such as, e.g., a linker, a hinge, an Fc domain or an albumin domain, to increase half-life, impart flexibility, allow for dimerization or other desired properties” (see SERMADIRAS at paragraph 0270). Thus, SERMADIRAS suggests that the Fc domain contributes to the activity, efficacy, stability, or in vivo half-life independently of the GIP/GLP-1-agonist function and suggests that the disclosed Fc domains may be fused to other proteins involved in the treatment of metabolic diseases. SERMADIRAS specifically points out the sequence of presently claimed SEQ ID NO: 7 (SERMADIRAS’ SEQ ID NO: 203) in paragraph 0348 and in a list of a finite number of ten Fc protein sequences (see SERMADIRAS at p. 125, under “Fc Sequences” – p. 130).
Furthermore, ARMSTRONG teaches that “[a]ny suitable half life extension protein can be used in fusion proteins according to embodiments of the invention. As used herein, the term ‘half life extension protein’ can be any protein or fragment thereof that is known to extend the half life of proteins to which it is fused. Examples of such half life extension proteins include, but are not limited to, human serum albumin (HSA), the constant fragment domain (Fc) of an immunoglobulin (Ig), or transferrin (Tf)” (see ARMSTRONG at paragraph 0074), and SERMADIRAS teaches that “the IgG Fc domain is an IgG4 Fc domain (SEQ ID NO: 203)” (see SERMADIRAS at paragraph 348). SERMADIRAS’ SEQ ID NO: 203 teaches the presently claimed SEQ ID NO: 7 with 100% identity. See Appendix. SERMADIRAS further claims the IgG4 Fc region in the disclosed heterologous polypeptide that comprises a linker, a hinge, an Fc domain, or a combination thereof. See SERMADIRAS at claim 69 and 58. Thus, ARMSTRONG in view of SERMADIRAS renders the claimed fusion polypeptide obvious.
“[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In reAller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of Americav.Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985)”. See MPEP 2144.05 (I) and (II).
On p. 7, second paragraph, Applicant argues that “[i]n contrast, Sermadiras explicitly discloses fusing the Fc domain to the C-terminus of the GIP/GLP-1 agonist (see paras. [0334]-[0336], [0398], and Fig. 1), which does not suggest the dimerization through the fusion partner of Fc region (i.e., GIP/GLP-1 agonist). In fact, it is well known in the art that the fusion position (N- vs. C-terminus) affects protein folding, stability, and biological activity. Thus, there would not have been motivation to extract a C-terminally fused Fc from Sermadiras and append it to the N-terminus of GDF15.”
As discussed under the 103 rejection above, ARMSTRONG teaches the claimed fusion polypeptide dimer comprising two fusion polypeptides, each fusion polypeptide comprising: GDF15 (Growth/differentiation factor 15) or a functional variant of GDF15, and Fc region of an immunoglobulin and SERMADIRAS teaches the Fc domain of claimed SEQ ID NO: 7. Specifically, ARMSTRONG teaches a fusion protein comprising: a. a half-life extension protein, b. a linker, and c. a GDF15 protein; wherein the fusion protein is arranged from N-terminus to C-terminus in the order (a)-(b)-(c) (see ARMSTRONG at claim 1) and SERMADIRAS teaches that a half-life extension protein is an IgG4 Fc domain having the same sequence as the claimed SEQ ID NO: 7. Thus, ARMSTRONG in view of SERMADIRAS renders the claimed fusion polypeptide obvious.
On p. 9, last paragraph, Applicant points to Tables 9 and 10 of the present specification to demonstrate unexpected results after the administration of the claimed fusion polypeptide dimer comprising two fusion polypeptides. However, ARMSTRONG also teaches a reduction in body weight of diet induced obese (DIO) mice during treatment with ARMSTRONG’s disclosed fusion proteins. See ARMSTRONG at FIG. 4 and paragraph 0028.
Nonetheless, the examples in Tables 9 and 10 are limited to a very specific GD515 structure, dosage and regimen in mice and is thus not commensurate in scope with the present claims. Additionally, there are only small differences in weight change between the IgG4 Fc and the IgG1 Fc GDF15 fusions, i.e. about a 3% difference in weight change between the IgG4 Fc and the IgG1 Fc GDF15 fusions at day 9 for similar treatments.
Conclusion
Claims 1, 6 – 12 and 16 – 20 are rejected.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Estella Gustilo whose telephone number is (703)756-1706. The examiner can normally be reached Monday - Friday 9:30 AM - 5:30 PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Gregory Emch can be reached at 571-272-8149. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ESTELLA M. GUSTILO/Examiner, Art Unit 1646
/PETER J REDDIG/Primary Examiner, Art Unit 1646
APPENDIX
Alignment with SEQ ID NO: 2
BEP57473
ID BEP57473 standard; protein; 98 AA.
XX
AC BEP57473;
XX
DT 11-JAN-2018 (first entry)
XX
DE Truncated mature GDF15 protein, SEQ ID 11.
XX
KW GDF15 protein; Growth differentiation factor 15;
KW carbohydrate metabolism disorder; cardiac reperfusion injury;
KW congestive heart failure; diabetic nephropathy; dimer;
KW lipid metabolism disorder; metabolic disorder; metabolic-gen.; mutein;
KW non-insulin dependent diabetes; obesity; prophylactic to disease;
KW protein production; recombinant protein; rheumatoid arthritis;
KW therapeutic.
XX
OS Homo sapiens.
XX
CC PN US2017327560-A1.
XX
CC PD 16-NOV-2017.
XX
CC PF 04-MAY-2017; 2017US-00586463.
XX
PR 10-MAY-2016; 2016US-0333886P.
XX
CC PA (JOHJ ) JANSSEN BIOTECH INC.
XX
CC PI Armstrong A, Connor JA, Furman J, Huang C, Hunter MJ;
CC PI Lin-Schmidt X, Nelson S, Rangwala S, Mullican S, Chavez JA;
XX
DR WPI; 2017-779563/78.
DR N-PSDB; BEP57568, BEP57569, BEP57570.
XX
CC PT New fusion protein comprising half-life extension protein, linker and
CC PT growth differentiation factor 15 protein used to treat or prevent
CC PT metabolic disorder e.g. type 2 diabetes, obesity, elevated insulin levels
CC PT and congestive heart failure.
XX
CC PS Claim 3; SEQ ID NO 11; 235pp; English.
XX
CC The present invention relates to a novel fusion protein comprising a half
CC -life extension protein, a linker and a growth differentiation factor 15
CC (GDF15) protein useful for treating or preventing metabolic disorders in
CC a subject. The fusion protein is arranged from N-terminus-C-terminus in
CC the order of half-life extension protein-linker-GDF15 protein. Also
CC described are: (1) a fusion protein comprising an amino acid sequence of
CC SEQ ID NO: 5 (BEP57467), SEQ ID NOs: 25-30 (BEP57487-BEP57492), SEQ ID
CC NO: 36 (BEP57468), SEQ ID NO: 37 (BEP57499), SEQ ID NO: 40 (BEP57502),
CC SEQ ID NO: 48 (BEP57510), SEQ ID NO: 55 (BEP57517), SEQ ID NO: 56
CC (BEP57518); SEQ ID NO: 59 (BEP57521), SEQ ID NO: 60 (BEP57522), SEQ ID
CC NOs: 64-75 (BEP57526-BEP57537), SEQ ID NO: 92 (BEP57554), SEQ ID NO: 113
CC (BEP57575), SEQ ID NO: 115 (BEP57577), SEQ ID NO: 117 (BEP57579), SEQ ID
CC NO: 119 (BEP57581), SEQ ID NO: 121 (BEP57583), SEQ ID NO: 123 (BEP57585),
CC SEQ ID NO: 125 (BEP57587), or SEQ ID NO: 127 (BEP57589); (2) an isolated
CC nucleic acid comprising either a nucleotide sequence encoding the fusion
CC protein; (3) a vector comprising the nucleic acid; (4) a host cell
CC comprising the nucleic acid molecule; (5) a method for producing the
CC fusion protein; (6) a dimer comprising two polypeptide chains, where each
CC chain comprises from N-terminus to C-terminus the fusion protein; and (7)
CC a polypeptide comprising an amino acid sequence of SEQ ID NOs: 7-11
CC (BEP57469-BEP57473). The metabolic disorder that can be treated by the
CC fusion protein includes type 2 diabetes, elevated glucose levels,
CC elevated insulin levels, obesity, dyslipidemia, diabetic nephropathy;
CC myocardial ischemic injury, congestive heart failure and rheumatoid
CC arthritis. The fusion protein exhibits increased solubility/stability and
CC improved pharmacokinetic profiles. The present sequence represents a
CC truncated mature GDF15 protein, used in the method for producing the
CC fusion protein of the invention.
XX
SQ Sequence 98 AA;
ALIGNMENT:
Query Match 100.0%; Score 536; Length 98;
Best Local Similarity 100.0%;
Matches 98; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 CRLHTVRASLEDLGWADWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVP 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 CRLHTVRASLEDLGWADWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVP 60
Qy 61 APCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI 98
||||||||||||||||||||||||||||||||||||||
Db 61 APCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI 98
Alignment with SEQ ID NO: 7
RESULT 3
BDD73777
ID BDD73777 standard; protein; 217 AA.
XX
AC BDD73777;
XX
DT 06-OCT-2016 (first entry)
XX
DE Human IgG4 Fc region, SEQ ID 203.
XX
KW Immunoglobulin G4; Immunoglobulin gamma 4; diabetes mellitus;
KW heavy chain constant region; hypoglycemia; metabolic-gen.;
KW non-insulin dependent diabetes; prophylactic to disease;
KW protein production; protein therapy; recombinant protein; therapeutic.
XX
OS Homo sapiens.
XX
CC PN WO2016131893-A1.
XX
CC PD 25-AUG-2016.
XX
CC PF 17-FEB-2016; 2016WO-EP053400.
XX
PR 18-FEB-2015; 2015US-0117587P.
XX
CC PA (ASTR ) MEDIMMUNE LTD.
CC PA (ASTR ) MEDIMMUNE LLC.
XX
CC PI Sermadiras I, Ravn P, Bednarek MA, Suckow A, Papworth M;
CC PI Bernard E;
XX
DR WPI; 2016-51813P/59.
DR N-PSDB; BDD74006.
XX
CC PT Isolated polypeptide in pharmaceutical composition used for treating or
CC PT preventing type-2 diabetes caused by hypoglycemia or impaired insulin,
CC PT and improving glycemic control and beta-cell functioning, and comprises
CC PT amino acid sequence.
XX
CC PS Example 11; SEQ ID NO 203; 158pp; English.
XX
CC The present invention relates to an isolated polypeptide used in a
CC pharmaceutical composition for treating or preventing hypoglycemic
CC conditions. The invention further relates to: (1) a method for preparing
CC polypeptide; (2) a pharmaceutical composition containing polypeptide and
CC carrier; (3) a kit containing pharmaceutical composition; and (4) a
CC method for treating or preventing a disease or a condition caused by
CC hypoglycemia or impaired insulin release. The disease or a disorder
CC include diabetes and type-2 diabetes. The invention also provides a
CC gastric inhibitory peptide or glucose-dependent insulinotropic
CC polypeptide (GIP)/glucagon-like peptide-1 (GLP-1) dual agonist fusion
CC proteins, synthetic and conjugated proteins for the treatment of
CC hypoglycemic conditions. The present sequence represents a human IgG4 Fc
CC region, forms a part of the fusion protein which is used in the
CC pharmaceutical composition for treating or preventing hypoglycemic
CC conditions.
XX
SQ Sequence 217 AA;
Query Match 100.0%; Score 1152; Length 217;
Best Local Similarity 100.0%;
Matches 216; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 APEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTK 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2 APEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTK 61
Qy 61 PREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYT 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 62 PREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYT 121
Qy 121 LPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 122 LPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL 181
Qy 181 TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG 216
||||||||||||||||||||||||||||||||||||
Db 182 TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG 217
Prosecution Insights