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 .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 12/15/2025 has been entered.
Status of the Claims
Claims 1, 3 – 12, and 14 – 20 were pending. Claims 1 and 12 have been amended, and claims 3 – 5 and 14 – 15 have been canceled. Claims 1, 6 – 12, and 16 – 20 are currently pending and are the subject of this Office Action.
Claim Objections
Previous objection, withdrawn: claim 1 was objected to because of the following informalities: GGGGS should be labeled with SEQ ID NO: 13.
In view of the claim amendments in the reply of 12/15/2025, this objection is withdrawn.
New objection Claim 1 is objected to because of the following informalities: the phrase on lines 9-10 “the functional variant of GDF15 is 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,” should be “the functional variant of GDF15 is a deletion variant in which 14 amino acids at positions 1 to 14 of the amino acid sequence of SEQ ID NO: 1 are deleted,”. Appropriate correction is required.
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).
Previous rejection, withdrawn: claims 1, 3 – 12, 14 – 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 TAGMOSE (US 2020/0261595 A1, filed 04/04/2018, an IDS reference).
In view of the claim amendments in the reply of 12/15/2025, this rejection is withdrawn.
New rejection, necessitated by claim amendments: 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).
The present application is directed to a fusion polypeptide, comprising GDF15 (Growth/differentiation factor 15) or a functional variant of GDF15, and Fc region of an immunoglobulin, wherein, the Fc region of the immunoglobulin is a single chain of human IgG4 Fc region of SEQ ID NO: 7, 8, or 9, and is linked to the N-terminus of the GDF15 or its functional variant, via a flexible peptide linker, the functional variant of GDF15 is 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, and the flexible peptide linker is represented by (GGGGS)n (SEQ ID NO: 13)n, wherein n is 1, 2, 3, 4, or 5.
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 paragraph 0008. 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. 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, 8, or 9.
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.
Regarding claims 1 and 12, 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 claim 1, 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 claim 7, ARMSTRONG discloses fusion proteins FP1s as intact dimers in serum. See paragraphs 0026 and 0037.
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, second paragraph, Applicant argues that “Armstrong is directed to GDF15 fusion proteins in which a half-life extension protein is fused to the N-terminus of GDF15. Armstrong discloses that "[i]n one general aspect, the invention relates to 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 para. [0008]. In contrast, Tagmose is directed to an insulin-Fc conjugate having a fundamentally different architecture, namely a construct in which two Fc monomers are connected to C-terminus of insulin molecule via a trivalent linking group (e.g., see Tagmose at paras. [0093]-[0120]). In these formulae of Tagmose, "Y" and "U", which are positioned at the C-terminus of insulin, represent trivalent linking groups, each of which is linked to two Fc monomers. See id. That is, the insulin-Fc conjugate of Tagmose comprises two Fc monomers per one insulin. Tagmose is concerned with Fc fusion proteins comprising polypeptides insulin (see para. [0054] and throughout), which is a completely different protein than GDF15 disclosed in Armstrong or the claimed invention. Thus, Applicant respectfully submits that the Office has not met its burden to establish that a skilled artisan would have been motivated to modify Armstrong based on Tagmose disclosing a completely different protein conjugate and architecture thereof.”
Although TAGMOSE may disclose a different architecture of the domains of the fusion protein, as Applicant points out, ARMSTRONG teaches the orientation as of the claimed fusion polypeptide and thus renders the claimed structure obvious. TAGMOSE was applied to show that the human IgG4 Fc domain is known in to be used in fusion polypeptides.
Nonetheless, the newly applied SERMADIRAS renders the presently claimed Fc domain obvious as discussed in the 103 rejection above, and ARMSTRONG in view of SERMADIRAS renders the claimed fusion polypeptide obvious as discussed above.
On p. 7, last paragraph – p. 8, second paragraph, Applicant argues that “[t]here would not have been a reasonable expectation of success to modify Armstrong based on the disclosures in Tagmose as alleged in the Office Action to arrive at the claimed invention. The Office Action failed to explain why a skilled artisan would have had a reasonable expectation of success to select only one Fc from two Fc monomers linked to a trivalent linking group of C-terminus of insulin as disclosed in Tagmose, and then modify GDF15 fusion protein of Armstrong to arrive at the claimed invention. A skilled artisan would have recognized numerous substantial challenges, with non-obvious solutions, including, but not limited to:
-biophysical differences for distinct proteins, namely GDF15 and insulin: folding
stability and solubility;
functional differences for distinct proteins, such as GDF15 and insulin: biological
activity; and
expression and purification differences.
A skilled artisan would readily appreciate that creating a fusion protein would
substantially change the function, stability, and preparation of the protein, which would not have been obvious. These differences in the biophysical properties of insulin versus GDF15 would pose entirely distinct challenges in designing and expressing a fusion protein and success in one would not be expected to inform the design of the other. As such, a person of ordinary skill in the art would not have been motivated to combine the disclosures of Amstrong and Tagmose with a reasonable expectation of success to arrive at the claimed invention. Thus, the claims would not have been obvious for at least the foregoing reasons.”
Applicant’s argument is not persuasive because ARMSTRONG teaches the structure of the fusion polypeptide of the present claims including the GDF15 domain, the linker, and an Fc domain. With the teachings of SERMADIRAS and routine experimentation in protein engineering, one having ordinary skill in the art can arrive to the invention of the present claims.
On p. 8, last paragraph – p. 11, last paragraph, Applicant argues that “the specification of the subject application demonstrates the unexpected results of the claimed invention over the closest cited reference, Armstrong, which further demonstrates the non-obviousness of the claims. Independent claims 1 and 12 have been amended to specify that the Fc region of the immunoglobulin is a single chain of human IgG4 Fc region of SEQ ID NO: 7, 8, or 9. As shown in Table 9 and Table 10 in the specification, there is a clear and unexpected difference in durability after a single administration with a fusion of IgG4 (Table 10). Specifically, with IgG4 Fc (Table 10), body weight continues to decrease even after Day 7 (red box), and the minimum body-weight level is maintained for a longer period (blue box). In contrast, with IgG1 Fc (Table 9), body weight remains unchanged or increases after Day 7. These results demonstrate that IgG4 Fc provides GDF15 with longer half-life than IgG1 Fc. However, Armstrong fails to provide any guidance or suggestion for preparing a fusion protein with IgG4 Fc to extend the half-life and therapeutic efficacy of GDF15. Further, Tagmose also fails to suggest advantages provided by a GDF15 IgG4 Fc fusion protein as demonstrated in the specification. Thus, Applicant submits that the specification demonstrates that the claimed invention as a whole would have been unexpected over the closest prior art and successfully rebuts any alleged prima facie case of obviousness, which Applicant disputes”.
Applicant’s argument has been fully considered but not found persuasive because the cited references teaches that the Fc domain extends the half-life of a protein that it is engineered on to. ARMSTRONG teaches “fusion proteins of GDF15 that demonstrate increased solubility/stability and exhibit features that indicate they can be used to treat or prevent metabolic diseases, disorders, or conditions. Furthermore, SERMADIRAS teaches that “half-life can be extended by the addition of an Fc domain”. See paragraph 0293.
Thus, the cited references teach the half-life extension of fusion proteins with the addition of an Fc domain, and SERMADIRAS teaches that the Fc domain is specifically IgG4 Fc having the sequence of SEQ ID NO: 7 (as presently claimed). Because the stability (increased half-life) of the claimed fusion polypeptide is directly attributed to the Fc region, the cited references render the results described by Applicant obvious.
Conclusion
Claims 1, 6 – 12, 16 – 20 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ESTELLA M. GUSTILO whose telephone number is (703)756-1706. The examiner can normally be reached Monday - Friday 9:00 AM - 5:00 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, JANET L. EPPS-SMITH can be reached at 571-272-0757. 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