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 .
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Specifically, no sequence identification has been provided for the sequence presented in Figure 24C of the instant specification filed 07/08/2025. Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
DETAILED ACTION
Status of Application/Election/Restrictions
Applicant’s election of Group I (claims 1-9 and 17) in the reply filed on October 28, 2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 10-16 and 18 are canceled. Claims 19 and 22 are amended. Claims 1-9, 17 and 19-28 are pending in this application. Claims 19-28 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. was treated as without traverse in the reply filed on October 28, 2025.
Claims 1-9 and 17 are under examination in this office action.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Drawings
The drawings are objected to because no sequence identification has been provided for the sequence presented in Figure 24C. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because of the following informalities: The use of the term “SUPERase” (p. 36, [00152]); ‘Eppendorf” (p. 36, [00153]), “SYBR” (p.36, [00154]); “EZ Reader”, “Microvette” (p. 36,[00155]); “Basler” (p. 36, [00156]; p. 37, [00157]) or “EthoVision” (p. 37, [00157]-[00158]), which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks. Appropriate correction is required.
Claim Objections
Claims 19-28 are objected to because of the following informalities: the status of the claims 19-28 is incorrect because these claims are withdrawn from consideration. Appropriate correction is required.
See MPEP 714 & 37 CFR 1.121.
“In the claim listing, the status of every claim must be indicated after its claim number by using one of the following identifiers in a parenthetical expression: (Original), (Currently amended), (Canceled), (Withdrawn), (Previously presented), (New), and (Not entered).”
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2-6, 8-9 and 17 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.
Claims 2-6, 8-9 and 17 are indefinite because:
i. It is unclear whether the claimed variant EPO polypeptide recited in claim 2 comprises the sequence of SEQ ID NO:3 with three amino acid substitutions at positions 20, 45 and 97 of SEQ ID NO:3 or the claimed variant EPO polypeptide comprises any sequences and with three amino acid substitutions corresponding to positions 20, 45 and 97 of SEQ ID NO:3.Thus, the claim is indefinite.
For examination purposes, the limitation “A variant EPO polypeptide comprising three amino acid sequence substitutions at position 20, 45 and 97 of SEQ ID NO:3” is interpreted as “A variant EPO polypeptide comprising any sequences and having three amino acid substitutions corresponding to positions 20, 45 and 97 of SEQ ID NO:3”.
ii. Claim 8 recites the limitation "the native carbohydrate moiety" in line 2 of the claim. There is insufficient antecedent basis for this limitation in the claim.
iii. The limitation “40% smaller in comparison to native human erythropoietin” recited in claim 9 is unclear because it is unclear whether the limitation “40% smaller” means that the three dimension conformation of the variant EPO molecule is 40% smaller than that of the native human EPO or the amino acid sequence in length of the claimed variant EPO molecule is 40% smaller than that of the native human EPO. Thus, claim 9 is indefinite.
iv. It is unclear whether the limitation “said variant” recited in claims 8-9 and the limitation “the variant” recited in the claims refer to the same variant, which renders the claims in definite.
v. The rest of claims are indefinite as depending from an indefinite claim.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-9 and 17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof.
Claim 1 is drawn to a polypeptide comprising the sequence of SEQ ID NO:1, or variants thereof. Claim 7 is drawn to a polypeptide comprising the sequence of SEQ ID NO:2 or variant thereof.
Claims 2-6, 8-9 and 17 are drawn to a variant EPO polypeptide comprising any sequences and having three amino acid substitutions corresponding to positions 20, 45 and 97 of SEQ ID NO:3. Claim 4 is directed to the variant EPO polypeptide further comprising a maltose binding protein sequence and claim 6 is directed to the variant EPO polypeptide further comprising a Factor Xa peptide sequence.
The claims 1 and 7 encompass a genus of variant polypeptides of SEQ ID NO:1 or 2.
The claims 2-6, 8-9 and 17 encompass a genus of variant EPO polypeptides comprising any sequences and having three amino acid substitutions corresponding to positions 20, 45 and 97 of SEQ ID NO:3. The claim 4 encompasses a genus of variant EPO polypeptide further comprising a genus of maltose binding protein sequence and the claim 6 encompass a genus of variant EPO polypeptide further comprising a genus of Factor Xa peptide sequence.
Applicant has not disclosed sufficient species for the broad genus of variant polypeptide of SEQ ID NO:1 or 2 or the broad genus of variant EPO polypeptide comprising structurally and functionally undefined sequences and with three amino acid substitutions corresponding to positions 20, 45 and 97 of SEQ ID NO:3.
The specification only describes:
i. QPO: K to Q substitutions at positions 20, 45 and 97 of wild type human EPO of SEQ ID NO:3 (i.e. SEQ ID NO:3 with K20Q, K45Q and K97Q) or the polypeptide of SEQ ID NO:1 or SEQ ID NO:2 (i.e.MBP/6x-His QPO fusion protein that can be cleaved by Factor Xa Protease) which has the property of retaining the activity of activating EPOR/CD131 heterodimer and mimicking CEPO’s inability to activate the EPOR homodimer, and can upregulate BDNF and EGR1 expression in PC12 cells or mouse hippocampus, or enhance memory recognition in 5xFAD mice (an animal model of Alzheimer’s disease) when compared to controls (see para. [00144]; [00166]-[00169]; [00182]-[0192]; Figures 3-5, 29 & 9-18; [0066]-[0072]; [0076]).
ii. RPO: K to R substitutions at positions 20, 45 and 97 of wild type human EPO of SEQ ID NO:3 (i.e. SEQ ID NO:3 with K20R, K45R and K97R) can only upregulate NRN1 and ARC but does not have the activity of upregulating BDNF expression and have no effects on object recognition memory test (ORMT test: a test of cognitive function), forced swim test (FST: a test for antidepressant activity), open field test (OFT: a test of general locomotor activity), novelty induced hypophagia test (NIHT: a test of chronic antidepressant activity) (see para. [00182]-[0192]; Figures 9-18).
However, the claims are not limited to the QPO (SEQ ID NO:3 with K20Q, K45Q and K97Q), or a polypeptide of SEQ ID NO:1 or SEQ ID NO:2 set forth above but also encompass a genus of structurally and functionally undefined variants of SEQ ID NO:1 or 2, a genus of structurally and functionally undefined variant EPO polypeptides comprising three amino acid substitutions at positions 20, 45 and 97 of SEQ ID NO:3, a genus of maltose binding protein sequence and a genus of a Factor Xa peptide sequence.
In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant is in possession of and what Applicant is claiming.
M.P.E.P. § 2163 instructs:
An invention described solely in terms of a method of making and/or its function may lack written descriptive support where there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function. . . .
An applicant may show possession of an invention by disclosure of drawings or structural chemical formulas that are sufficiently detailed to show that applicant was in possession of the claimed invention as a whole. . . .
An applicant may also show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics.”
This standard has not been met in this case. From the specification, it is clear that Applicant is in possession of QPO (SEQ ID NO:3 with K20Q, K45Q and K97Q), a polypeptide of SEQ ID NO:1 or SEQ ID NO:2. However, Applicant is not in possession of other structurally and functionally undefined variant polypeptides of SEQ ID NO:1 or 2 or structurally and functionally undefined variant EPO polypeptide comprising three amino acid substitutions at positions 20, 45 and 97 of SEQ ID NO:3.
Based on Applicant’s own admission, not all possible variants of SEQ ID NO:1 or 2 or substitutions can maintain the activity of QPO which has specific K to Q substitutions at positions 20, 45 and 97 of SEQ ID NO:3 on wild type human EPO in upregulating BDNF expression and enhancing memory recognition in 5xFAD mice because RPO (SEQ ID NO:3 with K20R, K45R and K97R) does not have the activity of upregulating BDNF in hippocampus or enhancing memory recognition in 5xFAD mice as QPO or EPO.
The specification does not teach the structural and functional relationship between the claimed genus of variants/variant EPO and the QPO (SEQ ID NO:3 with K20Q, K45Q and K97Q), or a polypeptide of SEQ ID NO:1 or SEQ ID NO:2 shown in Examples. The instant specification fails to provide sufficient descriptive information, such as definitive structural or functional features of the claimed genus of polypeptide variants of SEQ ID NO:1 or 2, the claimed genus of variant EPO polypeptides, the claimed genus of maltose binding protein sequence and the claimed genus of a Factor Xa peptide sequence. The specification provides no description of the conserved regions which are critical to the function of the genus claimed. There is no description of the sites at which variability may be tolerated because since a single amino acid change could abolish the binding ability of a molecule. For example, a substitution of lysine residue by glutamic acid at position 118 of acidic fibroblast growth factor results in a substantial loss of its biological activity including the binding ability to heparin and its receptor (Burgess et al. J of Cell Bio. 1990, 111:2129-2138). Even if an active or binding site were identified in the specification, they may not be sufficient, as the ordinary artisan would not immediately recognize that an active or binding site must assume the proper three-dimensional configuration to be active because conformation is dependent upon surrounding residues; i.e. substitution of non-essential residues can often destroy activity. In addition to a core determinant sequence, the protein-protein interaction also relies on the flanking or noncontiguous residues (see p. 445 the second column, first paragraph, Pawson et al. 2003, Science 300:445-452). The optimal binding motif for a domain is not necessarily suitable for physiological or in vivo interaction. The predictive data always need to be validated by actual analyses in cells (see p. 445, the third column, second paragraph, Pawson et al. 2003, Science 300:445-452). Alaoui-lsmaili teaches that designing a mutein having predictable activities is difficult because of the complexity of the interactions between ligands and receptors (Alaoui-lsmaili et al., Cytokine Growth Factor Rev. 2009; 20:501-507). For example, given the complexity of BMP-BMP receptor interactions, it is difficult to design BMPs with improved affinity and/or specificity for one specific receptor. More importantly, predicting the in vivo biological activity of such altered BMPs remains a challenging undertaking (see p. 502, right col., 2th paragraph). Further, when multiple mutations are introduced, there is even less predictability because Guo et al. teaches that the effects of mutations on protein function are largely additive (see p. 9207, left col., 2th paragraph, Guo et al., PNAS 2004; 101:9205-9210). The specification fails to teach what structures/amino acid sequences can or cannot be included/changed in all variants or variant EPO polypeptides in order to preserve the activity of QPO (SEQ ID NO:3 with K20Q, K45Q and K97Q), or a polypeptide of SEQ ID NO:1 or SEQ ID NO:2 in upregulating BDNF in hippocampus or enhancing memory recognition in 5xFAD mice.
The specification provides no information regarding the relation of structure of other variants of SEQ ID NO:1 or 2 or variant EPO polypeptides to the function of the QPO (SEQ ID NO:3 with K20Q, K45Q and K97Q) or the polypeptide of SEQ ID NO:1 or 2. Furthermore, the prior art does not provide compensatory structural or correlative teachings sufficient to enable one of skill to identify what other polypeptide variants of SEQ ID NO:1 or 2 or variant EPO polypeptides might be. Since the common characteristics/features of other variants of SEQ ID NO:1 or 2 or variant EPO polypeptides are unknown, a skilled artisan cannot envision the functional correlations of the genus with the claimed invention. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the genus of variants of SEQ ID NO:1 or 2, the genus of variant EPO polypeptides, the genus of maltose binding protein sequence and the genus of a Factor Xa peptide sequence.
Based on MPEP § 2161.01 and §2163, “to satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116”.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116).
As discussed above, the skilled artisan cannot envision the detailed chemical structure of the encompassed genus of variants of SEQ ID NO:1 or 2, the genus of variant EPO polypeptides, the genus of maltose binding protein sequence and the genus of a Factor Xa peptide sequence, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483.
Therefore, the claimed variant of SEQ ID NO:1 or 2 and the claimed variant EPO polypeptide have not met the written description provision of 35 U.S.C. §112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115). Applicant is directed to the Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, ¶ 1 "Written Description" Requirement. See MPEP § 2161.01 and 2163.
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 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.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-5, 7-9 and 17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Guyon et al. (U.S. Patent No. 8252743, issued on Aug 28, 2012, priority Nov 28, 2006; also published as WO2008065372).
Claims 1 and 7 are drawn to a polypeptide comprising the sequence of SEQ ID NO:1 or 2, or variants thereof.
Claims 2-5, 7-9 and 17 are drawn to a variant EPO polypeptide comprising any sequences and having three amino acid substitutions corresponding to positions 20, 45 and 97 of SEQ ID NO:3 and a composition comprising the claimed variant EPO polypeptide.
Guyon et al. (US8252743) teach a modified EPO polypeptide comprising the sequence of SEQ ID NO:79, which is 99.1% identical to instant SEQ ID NO:1 (see the sequence alignment below; col.). Guyon teaches that the modified EPO polypeptide contains one or more amino acid replacements including K20Q, K45Q and K97Q as recited in claims 2-3 (see col. 62, lines 50-60; col.63, line 3; col. 64, lines 4; 8; 14, table 3; col. 66, lines 63, 66; col. 67, line 5; 29-35; col. 69, line 9-15). Guyon teaches a fusion protein comprising the modified EPO polypeptide and a maltose binding protein sequence in claim 4 (col. 114, line 20-28), a histidine tag in claim 5 (col. 113, lines 42-56). Guyon also teaches a composition comprising the modified EPO (see col. 14, lines 1-67). The modified EPO polypeptide disclosed by Guyon meets the limitations recited in claims 1-5, 7-9 and 17 because the claimed variant polypeptide or variant EPO is not limited to a specific sequence. The modified EPO polypeptide disclosed by Guyon comprising 166 amino acid residues in length, which is the same size as in SEQ ID NO:1 or SEQ ID NO:3, and thus lacks the native carbohydrate moiety and is smaller than native human EPO as in claims 8-9 in view of paragraphs [0081]-[0082] and [0220] of the instant specification (based on the published application). Thus, claims 1-5, 7-9 and 17 are anticipated by Guyon et al. (US8252743).
SEQ ID NO:1
US-11-998-387A-79
Sequence 79, US/11998387A
Patent No. 8252743
GENERAL INFORMATION
APPLICANT: Thierry Guyon
APPLICANT: Gilles Borrelly
APPLICANT: Xavier Gallet
APPLICANT: Lila Drittanti
APPLICANT: Manuel Vega
TITLE OF INVENTION: MODIFIED ERYTHROPOIETIN POLYPEPTIDES AND USE THEREOF FOR TREATMENT
FILE REFERENCE: 119365-00049/931
CURRENT APPLICATION NUMBER: US/11/998,387A
CURRENT FILING DATE: 2009-02-25
PRIOR APPLICATION NUMBER: 60/861,615
PRIOR FILING DATE: 2006-11-28
NUMBER OF SEQ ID NOS: 310
SEQ ID NO 79
LENGTH: 166
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: EPO_77_K97Q
Query Match 99.1%; Score 843; Length 166;
Best Local Similarity 98.8%;
Matches 164; Conservative 2; Mismatches 0; Indels 0; Gaps 0;
Qy 1 APPRLICDSRVLERYLLEAQEAENITTGCAEHCSLNENITVPDTQVNFYAWKRMEVGQQA 60
|||||||||||||||||||:||||||||||||||||||||||||:|||||||||||||||
Db 1 APPRLICDSRVLERYLLEAKEAENITTGCAEHCSLNENITVPDTKVNFYAWKRMEVGQQA 60
Qy 61 VEVWQGLALLSEAVLRGQALLVNSSQPWEPLQLHVDQAVSGLRSLTTLLRALGAQKEAIS 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 VEVWQGLALLSEAVLRGQALLVNSSQPWEPLQLHVDQAVSGLRSLTTLLRALGAQKEAIS 120
Qy 121 PPDAASAAPLRTITADTFRKLFRVYSNFLRGKLKLYTGEACRTGDR 166
||||||||||||||||||||||||||||||||||||||||||||||
Db 121 PPDAASAAPLRTITADTFRKLFRVYSNFLRGKLKLYTGEACRTGDR 166
SEQ ID NO:1
ARW15606
(NOTE: this sequence has 3 duplicates in the database searched)
ID ARW15606 standard; protein; 166 AA.
XX
AC ARW15606;
XX
DT 07-AUG-2008 (first entry)
XX
DE Human modified erythropoietin (EPO) protein SEQ ID:19.
XX
KW diagnostic test; therapeutic; protein stabilization; protein therapy;
KW protein production; protein detection; mutagenesis; cytokine; anemia;
KW seizure disorder; multiple sclerosis; cerebral ischemia; hypotension;
KW cardiac arrest; ischemia; myocardial infarction; inflammation;
KW cognitive disorder; radiation injury; cerebral palsy;
KW neurodegenerative disease; Alzheimers disease; Parkinsons disease;
KW Leigh disease; hiv associated dementia; amnesia;
KW amyotrophic lateral sclerosis; alcoholism; mood disorder;
KW anxiety disorder; attention deficit hyperactivity disorder;
KW schizophrenia; autism; creutzfeldt jakob disease; trauma; brain injury;
KW spinal cord injury; head injury; macular degeneration; neuropathy;
KW diabetic neuropathy; diabetic retinopathy; glaucoma; ocular disease;
KW renal failure; cancer; vulnerary; vasotropic; tranquilizer;
KW ophthalmological; nootropic; neuroprotective; neuroleptic; nephrotropic;
KW muscular-gen.; hypertensive; cytostatic; cns-gen.; cerebroprotective;
KW cardiant; antiparkinsonian; antiinflammatory; anti-hiv; antidiabetic;
KW antianemic; antialcoholic; anticonvulsant; erythropoietin; EPO; mutein.
XX
OS Homo sapiens.
OS Synthetic.
XX
CC PN WO2008065372-A2.
XX
CC PD 05-JUN-2008.
XX
CC PF 27-NOV-2007; 2007WO-GB004520.
XX
PR 28-NOV-2006; 2006US-0861615P.
XX
CC PA (NAUT-) NAUTILUS BIOTECH SA.
XX
CC PI Guyon T, Borrelly G, Gallet X, Drittanti L, Vega M;
XX
DR WPI; 2008-H01039/44.
XX
CC PT New pharmaceutical composition comprises modified therapeutic polypeptide
CC PT or an active fragment of the polypeptide in a vehicle, useful for
CC PT treating disease or condition, e.g. anemia, seizure disorder,
CC PT hypotension, or inflammation.
XX
CC PS Claim 89; SEQ ID NO 19; 272pp; English.
XX
CC The present invention relates to novel modified erythropoietin (EPO)
CC polypeptides and other modified therapeutic polypeptides such as
CC granulocyte macrophage-colony stimulating factor (GM-CSF); macrophage-
CC colony stimulating factor (M-CSF); granulocyte colony-stimulating factor
CC (G-CSF); leukemia inhibitory factor (LIF); interleukin 1beta (IL-1beta);
CC interleukin-2 (IL-2); interleukin-3 (IL-3); interleukin-4 (IL-4);
CC interleukin-5 (IL-5); interleukin-6 (IL-6); oncostatin M (OSM); stem cell
CC factor (SCF); interferon-beta (IFN-beta) and interferon-gamma (IFN-
CC gamma). The polypeptides are modified to exhibit physical properties and
CC activities that differ from the corresponding unmodified polypeptides and
CC nucleic acid molecules encoding these polypeptides also are provided. The
CC invention provides methods for treatment and diagnosis using these
CC therapeutic polypeptides and also discloses a pharmaceutical composition
CC which comprises a modified therapeutic polypeptide or its active
CC fragment. The modified therapeutic polypeptide of the invention comprises
CC one or more amino acid replacements, insertions and deletions and
CC modifications at one or more of glycosylation sites compared to the
CC unmodified therapeutic polypeptide; exhibits increased resistance to
CC proteolysis; is not glycosylated and exhibits therapeutic activity. Also
CC claimed is a modified Erythropoietin (EPO) polypeptide; a nucleic acid
CC molecule encoding the modified EPO polypeptide; a vector comprising the
CC nucleic acid molecule which is linked to a promoter; a eukaryotic or a
CC prokaryotic host cell consisting of the nucleic acid molecule or the
CC vector which is useful for the production of a modified EPO polypeptide
CC and a method for expressing a modified EPO polypeptide which comprises
CC detection of the modified EPO polypeptide. The invention further
CC discloses that the modified therapeutic polypeptide is a cytokine and it
CC is present in the precursor or mature form. The pharmaceutical
CC composition of the invention is useful for diagnosing and treating
CC diseases such as anemia, seizure disorder, multiple sclerosis, cerebral
CC ischemia, hypotension, cardiac arrest, ischemia, myocardial infarction,
CC inflammation, cognitive disorder, radiation injury, cerebral palsy,
CC neurodegenerative disease, Alzheimers disease, Parkinsons disease, Leigh
CC disease, hiv associated dementia, amnesia, amyotrophic lateral sclerosis,
CC alcoholism, mood disorder, anxiety disorder, attention deficit
CC hyperactivity disorder, schizophrenia, autism, creutzfeldt jakob disease,
CC trauma, brain injury, spinal cord injury, head injury, macular
CC degeneration, neuropathy, diabetic neuropathy, diabetic retinopathy,
CC glaucoma, ocular disease, renal failure and cancer. The present sequence
CC is a Human modified erythropoietin (EPO) protein.
XX
SQ Sequence 166 AA;
Query Match 99.1%; Score 843; Length 166;
Best Local Similarity 98.8%;
Matches 164; Conservative 2; Mismatches 0; Indels 0; Gaps 0;
Qy 1 APPRLICDSRVLERYLLEAQEAENITTGCAEHCSLNENITVPDTQVNFYAWKRMEVGQQA 60
||||||||||||||||||||||||||||||||||||||||||||:|||||||||||||||
Db 1 APPRLICDSRVLERYLLEAQEAENITTGCAEHCSLNENITVPDTKVNFYAWKRMEVGQQA 60
Qy 61 VEVWQGLALLSEAVLRGQALLVNSSQPWEPLQLHVDQAVSGLRSLTTLLRALGAQKEAIS 120
||||||||||||||||||||||||||||||||||||:|||||||||||||||||||||||
Db 61 VEVWQGLALLSEAVLRGQALLVNSSQPWEPLQLHVDKAVSGLRSLTTLLRALGAQKEAIS 120
Qy 121 PPDAASAAPLRTITADTFRKLFRVYSNFLRGKLKLYTGEACRTGDR 166
||||||||||||||||||||||||||||||||||||||||||||||
Db 121 PPDAASAAPLRTITADTFRKLFRVYSNFLRGKLKLYTGEACRTGDR 166
Claim Rejections - 35 USC § 103
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 of this title, 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 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 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 the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Guyon et al. (US8252743; also published as WO2008065372) in view of Nemetz et al. (Chapter 14, p. 157-163, Book: Cell-Free Translation Systems edited by A.S. Spirin, 2002, Springer-Verlag Berlin Heidelbreg) and Jenny et al. (Protein Expression and Purification, 2003; 31:1-11. Doi:10.1016/S1046-5928(03)00168-2).
Guyon is set forth above but fails to teach that the modified EPO further comprising a Factor Xa peptide sequence recited in claim 7.
Nemetz et al. teach cloning EPO together with Factor Xa recognition sites that can be cleaved by Factor Xa protease can be used for releasing and purifying EPO (see p. 2, section: cloning).
Jenny et al. teach that Thrombin and factor Xa are the most frequently used proteases for improving the expression or folding of the protein of interest, and inserting Thrombin and factor Xa sequences recognized by Thrombin and factor Xa protease between the protein of interest and a tag or carrier for purification of the protein of interest, and the fusion partner with Factor Xa-catalyzed cleavage sequence (IEGR or IQGR) includes MBP and His-tag (see p.1, abstract; p. 3-4; p. 6-7, Table 3). Jenny teaches the use of Maltose Binding Protein (MBP) and/or a 6xHis tag for purification and a Factor Xa cleavage site (IEGR or IQGR) to release a specific EPO protein for research or therapeutic use.
A person of ordinary skill in the art would have recognized that selecting and applying the known factor Xa peptide sequence and the known technique disclosed by Nemetz and Jenny to the Guyon’s modified EPO polypeptide would have yielded the predictable result of variant EPO polypeptides comprising a factor Xa peptide sequence and resulted in an improved product for releasing and purification of EPO.
Using and including a factor Xa peptide sequence that can be recognized and cleaved by factor Xa protease in the Guyon’s modified EPO polypeptide including a fusion protein comprising the modified EPO polypeptide would improve the expression or folding of the Guyon’s modified EPO polypeptide and help purification of the Guyon’s modified EPO polypeptide for studies and therapeutic purposes, and expand application of the Guyon’s modified EPO polypeptide, and would increase the use of the Guyon’s modified EPO polypeptide for therapeutic purposes or treatment using the Guyon’s modified EPO polypeptide.
Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to select and apply the known the known factor Xa peptide sequence and the known technique disclosed by Nemetz and Jenny to the Guyon’s modified EPO polypeptide, and yield the predictable result of variant EPO polypeptides comprising a factor Xa peptide sequence for better expression or folding and purification of the Guyon’s modified EPO polypeptide for studies and therapeutic purposes.
Conclusion
NO CLAIM IS ALLOWED.
Sequence alignment
SEQ ID NO:1 1 APPRLICDSRVLERYLLEAQEAENITTGCAEHCSLNENITVPDTQVNFYAWKRMEVGQQA 60
SEQ ID NO:2 398 APPRLICDSRVLERYLLEAQEAENITTGCAEHCSLNENITVPDTQVNFYAWKRMEVGQQA 457
SEQ ID NO:3 1 APPRLICDSRVLERYLLEAKEAENITTGCAEHCSLNENITVPDTKVNFYAWKRMEVGQQA 60
SEQ ID NO:3/20/45/97Q 1 APPRLICDSRVLERYLLEAQEAENITTGCAEHCSLNENITVPDTQVNFYAWKRMEVGQQA 60
SEQ ID NO:1 61 VEVWQGLALLSEAVLRGQALLVNSSQPWEPLQLHVDQAVSGLRSLTTLLRALGAQKEAIS 120
SEQ ID NO:2 458 VEVWQGLALLSEAVLRGQALLVNSSQPWEPLQLHVDQAVSGLRSLTTLLRALGAQKEAIS 517
SEQ ID NO:3 61 VEVWQGLALLSEAVLRGQALLVNSSQPWEPLQLHVDKAVSGL-SLTTLLRALGAQKEAIS 119
SEQ ID NO:3/20/45/97Q 61 VEVWQGLALLSEAVLRGQALLVNSSQPWEPLQLHVDQAVSGL-SLTTLLRALGAQKEAIS 119
SEQ ID NO:1 121 PPDAASAAPLRTITADTFRKLFRVYSNFLRGKLKLYTGEACRTGDR 166
SEQ ID NO:2 518 PPDAASAAPLRTITADTFRKLFRVYSNFLRGKLKLYTGEACRTGDR 563
SEQ ID NO:3 120 PPDAASAAPLRTITADTFRKLFRVYSNFLRGKLKLYTGEACRTGDR 165
SEQ ID NO:3/20/45/97Q 120 PPDAASAAPLRTITADTFRKLFRVYSNFLRGKLKLYTGEACRTGDR 165
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Sathyanesan et al. (Transl. Psychi. 2018; 8:113. DOI 10.1038/s41398-018-0168-9) teaches carbamoylated erthropoietin (CEPO) and its effects on inducing expression of BDNF, VGF, Arc, TH and neuritrin in medial prefrontal cortex (mPFC) and hippocampal subfield and potential use for treatment of cognitive dysfunction in neuropsychiatric diseases (see abstract) and that the positions K45 and K20 are in close proximity to the high affinity active site residues and K97 is the only carbamoylated lysine that is close to the low affinity site (see p. 10, discussion).
WO2004022593 teaches a modified cytokine protein comprising the amino acid sequence of SEQ ID NO: 942, which is 99.1% identical to instant SEQ ID NO:1 (see the sequence alignment below).
ADL89608
(NOTE: this sequence has 6 duplicates in the database searched)
ID ADL89608 standard; protein; 166 AA.
XX
AC ADL89608;
XX
DT 03-JUN-2004 (first entry)
XX
DE Human modified cytokine protein #890.
XX
KW Human; cytokine; proteolysis; interferon; IFN; interleukin-10; IL-10;
KW long-chain cytokine family; short-chain cytokine family; infection;
KW allergy; heart disease; cancer; liver disorder; autoimmune disease;
KW growth disorder; diabetes; neurodegenerative disease; antimicrobial;
KW antiallergic; cytostatic; immunosuppressive; antidiabetic;
KW neuroprotective; mutant; mutein.
XX
OS Homo sapiens.
OS Synthetic.
XX
CC PN WO2004022593-A2.
XX
CC PD 18-MAR-2004.
XX
CC PF 08-SEP-2003; 2003WO-IB004347.
XX
PR 09-SEP-2002; 2002US-0409898P.
PR 21-MAR-2003; 2003US-0457135P.
XX
CC PA (NAUT-) NAUTILUS BIOTECH.
XX
CC PI Gantier R, Guyon T, Vega M, Drittanti L;
XX
DR WPI; 2004-248447/23.
XX
CC PT New modified cytokines with increased resistance to proteolysis, useful
CC PT for diagnosing and treating diseases such as infections, allergies, heart
CC PT diseases, cancer, liver disorders, autoimmune diseases or diabetes.
XX
CC PS Disclosure; SEQ ID NO 942; 316pp; English.
XX
CC The invention relates to modified cytokines that exhibit increased
CC resistance to proteolysis compared to unmodified cytokines. The invention
CC also relates to nucleic acid molecules encoding the cytokines, a
CC pharmaceutical composition comprising a nucleic acid molecule in a
CC pharmaceutical carrier, and a method of generating a protein or peptide
CC molecule having a predetermined property or activity, or a pre-selected
CC altered phenotype. The modified cytokine is selected from a member of the
CC interferons (IFNs)/interleukin (IL)-10 protein family, a member of the
CC long-chain cytokine family or a member of the short-chain cytokine
CC family. The composition and method are useful for diagnosing and treating
CC diseases such as infections, allergies, heart diseases, cancer, liver
CC disorders, autoimmune diseases, growth disorders, diabetes or
CC neurodegenerative diseases. This sequence represents a human modified
CC cytokine protein of the invention.
XX
SQ Sequence 166 AA;
Query Match 99.1%; Score 843; Length 166;
Best Local Similarity 98.8%;
Matches 164; Conservative 2; Mismatches 0; Indels 0; Gaps 0;
Qy 1 APPRLICDSRVLERYLLEAQEAENITTGCAEHCSLNENITVPDTQVNFYAWKRMEVGQQA 60
|||||||||||||||||||:||||||||||||||||||||||||||||||||||||||||
Db 1 APPRLICDSRVLERYLLEAKEAENITTGCAEHCSLNENITVPDTQVNFYAWKRMEVGQQA 60
Qy 61 VEVWQGLALLSEAVLRGQALLVNSSQPWEPLQLHVDQAVSGLRSLTTLLRALGAQKEAIS 120
||||||||||||||||||||||||||||||||||||:|||||||||||||||||||||||
Db 61 VEVWQGLALLSEAVLRGQALLVNSSQPWEPLQLHVDKAVSGLRSLTTLLRALGAQKEAIS 120
Qy 121 PPDAASAAPLRTITADTFRKLFRVYSNFLRGKLKLYTGEACRTGDR 166
||||||||||||||||||||||||||||||||||||||||||||||
Db 121 PPDAASAAPLRTITADTFRKLFRVYSNFLRGKLKLYTGEACRTGDR 166
WO2009152944 teaches a human EPO mature protein mutant comprising the amino acid sequence of SEQ ID NO: 19, which is 99.1% identical to instant SEQ ID NO:1 (see the sequence alignment below).
SEQ ID NO:1
ID AXX71688 standard; protein; 166 AA.
XX
AC AXX71688;
XX
DT 10-JUN-2010 (first entry)
XX
DE Human erythropoietin (EPO) mature protein mutant, SEQ ID 19.
XX
KW Erythropoietin ligand; acquired immune deficiency syndrome; anemia;
KW antianemic; antiinflammatory; antisickling; cancer; chronic inflammation;
KW cytostatic; genetic-disease-gen.; hematological-gen.; hemorrhage;
KW hemostatic; immunostimulant; iron metabolism disorder; metabolic-gen.;
KW mutein; neurological disease; neuroprotective; protein therapy;
KW sickle cell anemia; thalassemia; therapeutic.
XX
OS Homo sapiens.
OS Synthetic.
XX
FH Key Location/Qualifiers
FT Misc-difference 20
FT /note= "Wild-type Lys substituted by Gln"
XX
CC PN WO2009152944-A1.
XX
CC PD 23-DEC-2009.
XX
CC PF 29-MAY-2009; 2009WO-EP003862.
XX
PR 29-MAY-2008; 2008US-0130376P.
XX
CC PA (HANA-) HANALL PHARM CO LTD.
XX
CC PI Borrelly G, Drittanti L, Gallet X, Guyon T, Vega M;
XX
DR WPI; 2009-S67343/08.
XX
CC PT New modified erythropoietin polypeptide, comprises two amino acid
CC PT modifications at masked is-Hit residues masked by different glycosylation
CC PT sites, useful for treating a disease or condition, e.g. anemias.
XX
CC PS Claim 10; SEQ ID NO 19; 279pp; English.
XX
CC The present invention relates to novel modified erythropoietin (EPO)
CC polypeptides that exhibit increased protease resistance and
CC pharmaceutical compositions comprising them. The modified erythropoietin
CC polypeptide, comprises two amino acid modifications at the masked is-Hit
CC residues which are masked by different glycosylation sites; and one or
CC more additional amino acid modifications at un-masked is-Hit residue. The
CC invention also provides a nucleic acid sequence encoding the modified EPO
CC polypeptide; a vector, comprising the nucleic acid sequence; a host cell,
CC comprising the vector; a pharmaceutical composition, comprising the
CC modified EPO polypeptide and a method for treating a disorder that is
CC amenable to treatment by EPO. The modified therapeutic polypeptide
CC contains one or more additional amino acid modifications that contributes
CC to altered immunogenicity, carboxylation, hydroxylation, carbamylation,
CC sulfation, phosphorylation, oxidation, PEGylation or protease resistance.
CC The modified EPO polypeptide, nucleic acid molecule, pharmaceutical
CC compositions and methods are useful for treating anemias that accompany
CC renal failure, AIDS, malignancy, chronic inflammation, perioperative
CC surgeries; iron overload disorder; abnormal hemostasis; tissue protective
CC therapy; neurological condition, thalassemia, sickle cell anemia, the
CC anemia of prematurity, anemia that accompanies cis-platinum chemotherapy,
CC and anemia following intensive radiotherapy, chemotherapy and bone marrow
CC transplantation. The recombinant EPO polypeptide has improved half-life
CC and useful as a biotherapeutic agent. The present sequence is a Human
CC erythropoietin (EPO) mature protein mutant that has improved half-life
CC and increase protease resistance.
XX
SQ Sequence 166 AA;
Query Match 99.1%; Score 843; Length 166;
Best Local Similarity 98.8%;
Matches 164; Conservative 2; Mismatches 0; Indels 0; Gaps 0;
Qy 1 APPRLICDSRVLERYLLEAQEAENITTGCAEHCSLNENITVPDTQVNFYAWKRMEVGQQA 60
||||||||||||||||||||||||||||||||||||||||||||:|||||||||||||||
Db 1 APPRLICDSRVLERYLLEAQEAENITTGCAEHCSLNENITVPDTKVNFYAWKRMEVGQQA 60
Qy 61 VEVWQGLALLSEAVLRGQALLVNSSQPWEPLQLHVDQAVSGLRSLTTLLRALGAQKEAIS 120
||||||||||||||||||||||||||||||||||||:|||||||||||||||||||||||
Db 61 VEVWQGLALLSEAVLRGQALLVNSSQPWEPLQLHVDKAVSGLRSLTTLLRALGAQKEAIS 120
Qy 121 PPDAASAAPLRTITADTFRKLFRVYSNFLRGKLKLYTGEACRTGDR 166
||||||||||||||||||||||||||||||||||||||||||||||
Db 121 PPDAASAAPLRTITADTFRKLFRVYSNFLRGKLKLYTGEACRTGDR 166
US20080260820 teaches a human EPO mutein comprising the amino acid sequence of SEQ ID NO: 1529, which is 99.1% identical to instant SEQ ID NO:1 (see the sequence alignment below).
SEQ ID NO:1
ID ATS36124 standard; protein; 166 AA.
XX
AC ATS36124;
XX
DT 24-DEC-2008 (first entry)
XX
DE Human erythropoietin (EPO) mutein, SEQ ID 1529.
XX
KW protein therapy; therapeutic; viral infection; virucide; fibrosis;
KW antiinflammatory; condyloma; antimicrobial-gen.; dermatological; cancer;
KW cytostatic; growth disorder; growth-disorder-gen.;
KW acquired immune deficiency syndrome; immunostimulant; aging;
KW surgical procedure; surgical-gen.; congestive cardiomyopathy; cardiant;
KW liver transplantation; renal failure; nephrotropic; renal osteodystrophy;
KW osteoporosis; endocrine-gen.; osteopathic; achondroplasia; dysplasia;
KW inflammatory disease; Crohns disease; gastrointestinal-gen.;
KW immunosuppressive; short bowel syndrome; nutrition-disorder-gen.;
KW juvenile rheumatoid arthritis; antiarthritic; cystic fibrosis;
KW respiratory-gen.; male infertility; antiinfertility; uropathic; rickets;
KW osteopathic; down syndrome; nootropic; Spina bifida; neuroprotective;
KW genetic-disease-gen.; Noonan Syndrome; obesity; anorectic; fibromyalgia;
KW muscular-gen.; hepatitis c virus infection; hepatitis B virus infection;
KW hepatotropic; hairy cell leukemia; hematological-gen.; immunomodulator;
KW lymphoma; follicle center lymphoma; kaposis sarcoma; pulmonary fibrosis;
KW liver fibrosis; Turners syndrome; prader-willi syndrome; thalassemia;
KW erythropoietin; mutein.
XX
OS Homo sapiens.
OS Synthetic.
XX
CC PN US2008260820-A1.
XX
CC PD 23-OCT-2008.
XX
CC PF 19-APR-2007; 2007US-00788836.
XX
PR 19-APR-2007; 2007US-00788836.
XX
CC PA (BORR/) BORRELLY G.
CC PA (CHAU/) CHAUCHARD C.
CC PA (DRIT/) DRITTANTI L.
CC PA (VEGA/) VEGA M.
XX
CC PI Borrelly G, Chauchard C, Drittanti L, Vega M;
XX
DR WPI; 2008-M78313/75.
XX
CC PT New oral dosage formulation comprises a therapeutic polypeptide, tablet
CC PT or capsule, useful for treating a disease or condition, e.g. viral
CC PT infection, a fibrotic disorder, condylomata acuminate, cancer, and a
CC PT growth deficiency disorder.
XX
CC PS Claim 18; SEQ ID NO 1529; 120pp; English.
XX
CC The present invention relates to novel oral dosage formulations
CC comprising protease-resistant therapeutic peptides and their uses. In the
CC oral dosage formulation above, the therapeutic polypeptide contains one
CC or two amino acid sequence substitutions that render it more protease
CC resistant than in the absence of the modifications. The therapeutic
CC polypeptide is an interleukin (IL)-10, an interferon beta, an interferon
CC alpha, an interferon gamma, granulocyte colony stimulating leukemia
CC inhibitory factor, a growth hormone, ciliary neurotrophic factor, leptin,
CC insulin, oncostatin M, relaxin, IL-6, IL-12, erythropoietin, granulocyte-
CC macrophage colony stimulating factor, IL-2, IL-3, IL-4, IL-5, IL-13, F1t3
CC ligand, a monoclonal antibody or its fragment or a stem cell factor. The
CC invention also provides a tablet or capsule comprising 10-100 mg of an
CC interferon alpha (IFN-a), where the IFN-alpha is protease resistant by
CC virtue of its modifications and a method for treating a disease or
CC condition, comprising administering the oral dosage formulation of a
CC modified therapeutic polypeptide. The dosage formulation is useful for
CC treating viral infections, fibrotic disorders, condylomata acuminate,
CC cancer, growth deficiency disorders, AIDS, aging, impaired immune
CC function of HIV-infected subjects, catabolic illness, surgical recovery,
CC congestive cardiomyopathy, liver transplantation, liver regeneration
CC after hepatectomy, chronic renal failure, renal osteodystrophy,
CC osteoporosis, achondroplasia/hypochondroplasia, skeletal dysplasia,
CC chronic inflammatory disorder, Crohn's disease, short bowel syndrome,
CC juvenile chronic arthritis, cystic fibrosis, male infertility, X-linked
CC hypophosphatemic rickets, Down's syndrome, Spina bifida, Noonan Syndrome,
CC obesity, impaired muscle strength, fibromyalgia, hepatitis C infection,
CC hepatitis B infection, hairy cell leukemia, malignant lymphoma,
CC follicular lymphoma, AIDS-related Kaposi sarcoma, idiopathic pulmonary
CC fibrosis, liver fibrosis, renal fibrosis, Turner's syndrome, intrauterine
CC growth retardation, idiopathic short stature, Prader Willi syndrome, and
CC thalassemia. The present sequence is a Human erythropoietin (EPO) mutein,
CC used in the scope of the invention.
XX
SQ Sequence 166 AA;
4
ID AWO44428 standard; p
Query Match 99.1%; Score 843; Length 166;
Best Local Similarity 98.8%;
Matches 164; Conservative 2; Mismatches 0; Indels 0; Gaps 0;
Qy 1 APPRLICDSRVLERYLLEAQEAENITTGCAEHCSLNENITVPDTQVNFYAWKRMEVGQQA 60
||||||||||||||||||||||||||||||||||||||||||||:|||||||||||||||
Db 1 APPRLICDSRVLERYLLEAQEAENITTGCAEHCSLNENITVPDTKVNFYAWKRMEVGQQA 60
Qy 61 VEVWQGLALLSEAVLRGQALLVNSSQPWEPLQLHVDQAVSGLRSLTTLLRALGAQKEAIS 120
||||||||||||||||||||||||||||||||||||:|||||||||||||||||||||||
Db 61 VEVWQGLALLSEAVLRGQALLVNSSQPWEPLQLHVDKAVSGLRSLTTLLRALGAQKEAIS 120
Qy 121 PPDAASAAPLRTITADTFRKLFRVYSNFLRGKLKLYTGEACRTGDR 166
||||||||||||||||||||||||||||||||||||||||||||||
Db 121 PPDAASAAPLRTITADTFRKLFRVYSNFLRGKLKLYTGEACRTGDR 166
KR2008094312 teaches a human EPO mutant polypeptide comprising the amino acid sequence of SEQ ID NO: 1529, which is 99.1% identical to instant SEQ ID NO:1 (see the sequence alignment below).
SEQ ID NO:1
ID AWO44428 standard; protein; 166 AA.
XX
AC AWO44428;
XX
DT 04-AUG-2022 (revised)
DT 23-JUL-2009 (first entry)
XX
DE Human EPO mutant polypeptide K20Q, SEQ ID 1529.
XX
KW protein therapy; therapeutic; prophylactic to disease;
KW metabolic disorder; metabolic-gen.; inflammatory disease;
KW antiinflammatory; autoimmune disease; immunosuppressive; viral infection;
KW virucide; antimicrobial-gen.; hematological disease; hematological-gen.;
KW heart disease; cardiant; neuropathy; neuroprotective;
KW gastrointestinal disease; gastrointestinal-gen.; cancer; cytostatic;
KW obesity; anorectic; nutrition-disorder-gen.; EPO; Erythropoietin ligand;
KW mutein.
XX
OS Homo sapiens.
OS Synthetic.
XX
FH Key Location/Qualifiers
FT Misc-difference 20
FT /note= "Wild-type Lys substituted by Gln"
XX
CC PN KR2008094312-A.
XX
CC PD 23-OCT-2008.
XX
CC PF 19-APR-2007; 2007KR-00038557.
XX
PR 19-APR-2007; 2007KR-00038557.
XX
CC PA (NAUT-) NAUTILUS BIOTECH.
XX
CC PI Borrelly G, Chauchard C, Drittanti L, Vega M;
XX
DR WPI; 2009-E78925/23.
XX
CC PT Oral dosage formulation for preventing and treating diseases e.g. cancer,
CC PT comprises therapeutic polypeptide having amino acid substitutions and
CC PT showing higher protease resistance than therapeutic polypeptide without
CC PT variation.
XX
CC PS Claim 18; SEQ ID NO 1529; 1901pp; Korean.
XX
CC The present invention relates to oral dosage formulations comprising
CC protease-resistant polypeptides. The present invention provides a method
CC for treating or preventing diseases by administering the oral dose
CC formulation. The present invention further provides refinement or
CC capsule, for e.g., enteric coated. In the invention, the polypeptides are
CC selected from interleukin-10 (IL-10), interferon-beta, interferon alpha,
CC interferon-gamma, granulocyte colony-stimulating factor (G-CSF), leukemia
CC inhibitory factor (LIF), growth hormone (GH), ciliary neurotrophic factor
CC (CNTF), leptin, insulin, oncostatin M, relaxin, interleukin-6 (IL-6),
CC interleukin-12 (IL-12), erythropoietin (EPO), granulocyte-macrophage
CC colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), interleukin-3
CC (IL-3), interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-13 (IL-
CC 13), Flt3 ligand, monoclonal antibody or its fraction and stem cell
CC factor. The polypeptides used in the formulations comprise mutation in
CC the amino acid sequence when compared to its wild-type sequence. In the
CC invention, the diseases are selected from metabolic disease,
CC proliferative disease, inflammatory disease, autoimmune disease, viral
CC infection, microbism, blood disease, heart disease, neuropathy,
CC gastrointestinal disease, cancer, obesity, etc. The present sequence is a
CC human EPO mutant polypeptide used in the invention.
CC
CC Revised record issued on 04-AUG-2022 : Addition of DWPI-enhanced title
CC (PT field).
XX
SQ Sequence 166 AA;
Query Match 99.1%; Score 843; Length 166;
Best Local Similarity 98.8%;
Matches 164; Conservative 2; Mismatches 0; Indels 0; Gaps 0;
Qy 1 APPRLICDSRVLERYLLEAQEAENITTGCAEHCSLNENITVPDTQVNFYAWKRMEVGQQA 60
||||||||||||||||||||||||||||||||||||||||||||:|||||||||||||||
Db 1 APPRLICDSRVLERYLLEAQEAENITTGCAEHCSLNENITVPDTKVNFYAWKRMEVGQQA 60
Qy 61 VEVWQGLALLSEAVLRGQALLVNSSQPWEPLQLHVDQAVSGLRSLTTLLRALGAQKEAIS 120
||||||||||||||||||||||||||||||||||||:|||||||||||||||||||||||
Db 61 VEVWQGLALLSEAVLRGQALLVNSSQPWEPLQLHVDKAVSGLRSLTTLLRALGAQKEAIS 120
Qy 121 PPDAASAAPLRTITADTFRKLFRVYSNFLRGKLKLYTGEACRTGDR 166
||||||||||||||||||||||||||||||||||||||||||||||
Db 121 PPDAASAAPLRTITADTFRKLFRVYSNFLRGKLKLYTGEACRTGDR 166
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHANG-YU WANG whose telephone number is (571)272-4521. The examiner can normally be reached on Monday-Thursday, 7:00am-5:00pm EST.
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Chang-Yu Wang
November 15, 2025
/CHANG-YU WANG/Primary Examiner, Art Unit 1675