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 .
Claim Status
Claims 98 and 112-120 are pending; claims 98, 117, and 119 were amended in the Reply filed 11/13/2025. Claims 98 and 112-120 are presently considered.
Election/Restrictions
Applicant’s election without traverse of Group IV (original claim 98) and the species of claim 98 utilizing a set of polynucleotides encoding VWF-034 (SEQ ID NO: 92) and FVIII169 (SEQ ID NO: 88) in HEK293 cells in the reply filed on 6/06/2025 was previously acknowledged.
The elected species has been understood as follows:
The elected species (or subgenus of patentably indistinct variants) is a method of making a chimeric molecule, wherein the method comprises transfecting HEK293 cells with a set of polynucleotides capable of expressing a first polynucleotide corresponding to VWF-034 (SEQ ID NO: 92) and a second polynucleotide corresponding to FVIII169 (SEQ ID NO: 88).
Following extensive search and examination, the originally elected species has been deemed free of the prior art, but not allowable in view of previously issued patents reciting patentably indistinct subject matter (see non-statutory double patenting rejections, below).
Per MPEP § 803.02(III), Examination was extended to a non-elected species, namely a method of transfecting HEK293 cells with a set of polynucleotides comprising a modified FVIII and VWF protein as suggested by US2011/0183907A1. Following extensive search and examination, the non-elected species was deemed obvious in view of the prior art as applied below under 35 USC §103. Per MPEP § 803.02(III), claims directed to other nonelected species have been withdrawn.
Currently claims 98 and 112-120 are presently considered.
Priority
The priority claim to US Provisional 61/840,872 as filed 6/28/2013 is acknowledged.
Information Disclosure Statement
The IDS filed 11/13/2025 is acknowledged and presently considered.
Claim Interpretation
For purposes of examination, the claim scope has been interpreted as set forth below per the guidance set forth at MPEP § 2111. If Applicant disputes any interpretation, Applicant is invited to unambiguously identify any alleged misinterpretations or specialized definitions in the subsequent response to the instant action. Applicant is advised that a specialized definition should be properly supported and specifically identified (see, e.g., MPEP § 2111.01(IV), describing how Applicant may act as their own lexicographer).
Claim 98 is representative of the pending claim scope and is directed to a method. In the prior Reply filed 6/06/2025, Claim 98 was amended as follows:
98. A method of making a chimeric molecule, comprising transfecting one or more host cells with [[the]]a polynucleotide or set of polynucleotides expressing the chimeric molecule in the host cell, wherein the chimeric molecule comprises (i) a first polypeptide comprising a von Willebrand Factor (VWF) protein, a heterologous moiety (H1), an extended length polypeptide (XTEN), and a VWF linker connecting the VWF protein with the heterologous moiety, wherein the VWF linker comprises a thrombin cleavage site which comprises X-V-P-R (SEQ ID NO: 3), wherein X is an aliphatic amino acid and (ii) and a second polypeptide chain comprising a FVIII protein and an XTEN sequence;
wherein the XTEN sequence is connected to the VWF protein, the heterologous moiety (H1), the VWF linker, or any combination thereof.
In the most recent Reply filed 11/13/2025, claim 98 was amended as follows:
98. (Currently Amended) A method of making a chimeric molecule, comprising transfecting one or more host cells with a polynucleotide or set of polynucleotides encoding (i) a first polypeptide chain comprising a von Willebrand Factor (VWF) protein, a heterologous moiety (H1), an extended length polypeptide (XTEN) sequence, and a VWF linker connecting the VWF protein with the heterologous moiety, wherein the VWF linker comprises a thrombin cleavage site which comprises X-V-P-R (SEQ ID NO: 3), wherein X is an aliphatic amino acid and (ii) and a second polypeptide chain comprising a FVIII protein and an XTEN sequence,
subsequently expressing the first polypeptide chain and the second polypeptide chain in the host cell, such that the host cell expresses a chimeric molecule comprising the first polypeptide chain and the second polypeptide chain, wherein the first polypeptide chain and the second polypeptide chain are associated by a disulfide bond;
wherein the XTEN sequence is connected to (i) the VWF protein and the heterologous moiety, (ii) the heterologous moiety [[(H1)]]and the VWF linker, or (ii) the VWF linker and the VWF protein; and
wherein the XTEN sequences comprise multiple units of non-overlapping sequences of a single motif family selected from the group consisting of SEQ ID NOs: 49-78.
The applicable claim interpretation is discussed below.
The phrase “chimeric molecule” is interpreted in view of the description provided at ¶[0038] and ¶[0069] of the Specification as filed 7/25/2023, and is understood to read upon a molecule comprising “two different” polypeptide chains meeting the structural limitations set forth at claim 98.
The “first polypeptide chain” is understood to comprise a VWF protein, a first XTEN sequence, a heterologous moiety (H1) (i.e., a first immunoglobulin constant region in the elected species), and a “VWF linker” that “connect[s] the VWF protein with the heterologous moiety”.
Regarding the relative position of the VWF linker, amended claim 98 recites and requires
…a VWF linker connecting the VWF protein with the heterologous moiety…
Although the term “connecting” does not require direct, uninterrupted covalent linkage between VWF linker and either the VWF protein or H1 per the description of “connected” (see, e.g., Spec. filed 7/25/2023 at ¶[0072]) and exemplified arrangements (see, e.g., Spec. filed 7/25/2023 at ¶[0088]), it is reasonably inferred that the VWF linker must be located between the VWF protein sequence and the heterologous moiety. This interpretation is consistent with the subsequent recitation at claim 98 referring to “…wherein the XTEN sequence is connected to….”. In addition, “connected” includes
…insertion of the whole first amino acid sequence (or the second amino acid sequence) into any two amino acids in the second amino acid sequence (or the first amino acid sequence, respectively).
(see, e.g., Spec. filed 7/25/2023 at ¶[0072])
Accordingly, “connecting” is broadly defined.
The structure of the “VWF linker” is understood to comprise:
…a thrombin cleavage site comprising X-V-P-R (SEQ ID NO: 3), wherein X is an aliphatic amino acid…
Accordingly, the VWF linker is understood to not necessarily require the sequence of “Glu720 to Arg740 corresponding to full-length mature FVIII (SEQ ID NO: 16)” (i.e., “EDSYEDISAYLLSKNNAIEPR”) or the exact sequence of SEQ ID NO: 25 (“LVPR”), which is understood to be a thrombin cleavage sequence (see, e.g., Spec. filed 9/20/2021 at ¶[0005], instant SEQ ID NO: 31), or to otherwise require the sequence of (Gly4Ser)7. Furthermore, as claimed, the “VWF linker” does not have a maximum length, and no particular order of components is recited or required. Accordingly, the “VWF linker” encompasses any sequence comprising “X-V-P-R”, wherein “X” is an aliphatic amino acid.
Regarding the structure of the VWF protein as claimed, the phrase “von Willebrand Factor (VWF) protein” is functionally defined in the originally filed disclosure (see, e.g., Spec. filed 7/25/2023 at ¶¶[00103] on p. 36 to [0101] on p. 46). The term includes “full-length” and “functional VWF fragments. . . . capable of inhibiting binding of endogenous VWF to FVIII” (see id.). The “functional” fragments are interpreted as proteins that comprise a D’ domain and a D3 domain, wherein the D’ domain comprises any sequence sharing at least 60% identity to amino acids 764 to 866 of SEQ ID NO: 2; and wherein the D3 domain comprises an amino acid sequence sharing at least 60% identity to amino acids 867 to 1240 of SEQ ID NO: 2 (see, e.g., Spec. filed 7/25/2023 at ¶¶[00103] on p. 36 to [0101] on p. 46). Accordingly, a VWF protein is understood to be a protein capable of inhibiting binding of endogenous VWF to FVIII” (see, e.g., id.), which is presumably any sequence sharing at least 60% identity with
SLSCRPPMVKLVCPADNLRAEGLECTKTCQNYDLECMSMGCVSGCLCPPGMVRHENRCVALERCPCFHQGKEYAPGETVKIGCNTCVCRDRKWNCTDHVCDAT
(D’ Domain of SEQ ID NO: 2 from 764 to 866);
and further comprises a sequence at least 60% identical to the sequence:
CSTIGMAHYLTFDGLKYLFPGECQYVLVQDYCGSNPGTFRILVGNKGCSHPSVKCKKRVTILVEGGEIELFDGEVNVKRPMKDETHFEVVESGRYIILLLGKALSVVWDRHLSISVVLKQTYQEKVCGLCGNFDGIQNNDLTSSNLQVEEDPVDFGNSWKVSSQCADTRKVPLDSSPATCHNNIMKQTMVDSSCRILTSDVFQDCNKLVDPEPYLDVCIYDTCSCESIGDCACFCDTIAAYAHVCAQHGKVVTWRTATLCPQSCEERNLRENGYECEWRYNSCAPACQVTCQHPEPLACPVQCVEGCHAHCPPGKILDELLQTCVDPEDCPVCEVAGRRFASGKKVTLNPSDPEHCQICHCDVVNLTCEACQEP
(D3 domain, 867-1240 of SEQ ID NO: 2).
This genus of VWF proteins is understood to encompass full-length VWF proteins, and all members of the genus are presumed fully capable of inhibiting binding of endogenous VWF to FVIII” (see, e.g., Spec. filed 7/25/2023 at ¶¶[00103] on p. 36 to [0101] on p. 46), wherein “the D’ domain and D3 domain are capable of binding to a FVIII protein” (see, e.g., id.).
Regarding VWF protein functionality, Examiner notes that one or ordinary skill in the art would recognize that VWF is an art-recognized “coagulation factor” (see, e.g., US2010/0120664 at ¶[0084]). One of ordinary skill in the VWF arts would reasonably recognize and appreciate the function of the D’ and D3 domains of VWF, which are the domains of VWF that bind to FVIII and are required to prolong FVIII half-life (see, e.g., WO 2011/060242 A21 at 3 at 4th-5th full ¶¶).
Regarding the structure of the XTEN present in the originally elected species: In the originally elected species, any “XTEN” sequence within the originally elected species is understood to be instant SEQ ID NO: 43, which is understood to be AE288:
GTSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAP
Accordingly, each XTEN sequence is understood to comprise at least instant AE288.
Regarding the general structure of “XTEN” sequences in the absence of identification using a SEQ ID NO: The term “XTEN” does not define any particular set or subset of unambiguous sequences for reasons set forth previously on record, and those discussion are incorporated herein (see, e.g., Action mailed 8/13/2025 at pages 13-17, 22-33).
Regarding the “heterologous moiety” (HI): Claim 98 recites and requires “a heterologous moiety (H1)”, which is defined in the Specification as including at least
….an immunoglobulin constant region or a portion thereof, albumin, albumin-binding moiety, PAS, HAP, transferrin or a fragment thereof, polyethylene glycol (PEG), hydroxyethyl starch (HES), PSA, the C-terminal peptide (CTP) of the p subunit of human chorionic gonadotropin, or any combination thereof.
(see, e.g., Spec. filed 7/25/2023 at ¶¶[0015]-[0016]).
Accordingly, the “heterologous moiety” as recited at independent claim 98 is understood to broadly encompass the exemplified definition set forth in the originally filed disclosure. However, independent claim 98 also requires that the heterologous moieties present necessarily and inherently be capable of being encoded by polynucleotides (see, e.g., instant claim 98). This limits the potential heterologous moieties to polypeptide sequences. The “heterologous moiety” present in the originally elected species is understood to be an immunoglobulin constant region.
Regarding the heterologous moiety consisting of an Immunoglobulin Constant Region, this term is interpreted consistently with the description (see, e.g., Spec. filed 7/25/2023 at § II.C.3.a, ¶¶[0111]-[0124]), wherein a “[a]n immunoglobulin constant region used herein can include all domains and the hinge region or portions thereof” (see, e.g., id. at ¶[0115]). Therefore, references to an “immunoglobulin constant region” reasonably encompass “portions thereof” of the immunoglobulin constant region (id.), including the CH2 domain, CH3 domain, hinge region, Fc region, etc. (id.).
A “portion thereof” is recited at claims 117-120, and is not unambiguously defined in the claim or on record. Accordingly, the phrase is given the literal interpretation of “a portion”, and is understood to include any single amino acid, dipeptide, tripeptide, etc. of any immunoglobulin constant region known in the prior art.
The “second polypeptide chain” is understood to comprise a FVIII protein and a second XTEN sequence.
The second polypeptide chain comprises an FVIII protein: “FVIII protein” is interpreted in view of the disclosure (see, e.g., Spec. filed 7/25/2023 at ¶¶[0160], [0166]-[0180]).
The originally elected species comprises VWF-034: VWF-034 (SEQ ID NO: 92. 1778 amino acids)2,3,4,5 present in the originally elected species has the following sequence:
MIPARFAGVLLALALILPGTLCAEGTRGRSSTARCSLFGSDFVNTFDGSMYSFAGYCSYLLAGGCQKRSFSIIGDFQNGKRVSLSVYLGEFFDIHLFVNGTVTQGDQRVSMPYASKGLYLETEAGYYKLSGEAYGFVARIDGSGNFQVLLSDRYFNKTCGLCGNFNIFAEDDFMTQEGTLTSDPYDFANSWALSSGEQWCERASPPSSSCNISSGEMQKGLWEQCQLLKSTSVFARCHPLVDPEPFVALCEKTLCECAGGLECACPALLEYARTCAQEGMVLYGWTDHSACSPVCPAGMEYRQCVSPCARTCQSLHINEMCQERCVDGCSCPEGQLLDEGLCVESTECPCVHSGKRYPPGTSLSRDCNTCICRNSQWICSNEECPGECLVTGQSHFKSFDNRYFTFSGICQYLLARDCQDHSFSIVIETVQCADDRDAVCTRSVTVRLPGLHNSLVKLKHGAGVAMDGQDIQLPLLKGDLRIQHTVTASVRLSYGEDLQMDWDGRGRLLVKLSPVYAGKTCGLCGNYNGNQGDDFLTPSGLAEPRVEDFGNAWKLHGDCQDLQKQHSDPCALNPRMTRFSEEACAVLTSPTFEACHRAVSPLPYLRNCRYDVCSCSDGRECLCGALASYAAACAGRGVRVAWREPGRCELNCPKGQVYLQCGTPCNLTCRSLSYPDEECNEACLEGCFCPPGLYMDERGDCVPKAQCPCYYDGEIFQPEDIFSDHHTMCYCEDGFMHCTMSGVPGSLLPDAVLSSPLSHRSKRSLSCRPPMVKLVCPADNLRAEGLECTKTCQNYDLECMSMGCVSGCLCPPGMVRHENRCVALERCPCFHQGKEYAPGETVKIGCNTCVCRDRKWNCTDHVCDATCSTIGMAHYLTFDGLKYLFPGECQYVLVQDYCGSNPGTFRILVGNKGCSHPSVKCKKRVTILVEGGEIELFDGEVNVKRPMKDETHFEVVESGRYIILLLGKALSVVWDRHLSISVVLKQTYQEKVCGLCGNFDGIQNNDLTSSNLQVEEDPVDFGNSWKVSSQCADTRKVPLDSSPATCHNNIMKQTMVDSSCRILTSDVFQDCNKLVDPEPYLDVCIYDTCSCESIGDCAAFCDTIAAYAHVCAQHGKVVTWRTATLCPQSCEERNLRENGYEAEWRYNSCAPACQVTCQHPEPLACPVQCVEGCHAHCPPGKILDELLQTCVDPEDCPVCEVAGRRFASGKKVTLNPSDPEHCQICHCDVVNLTCEACQEPISGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPDIGGGGGSGGGGSLVPRGSGGDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
The originally elected species comprises FVIII169: FVIII169 (SEQ ID NO: 88, 1978 amino acids)6,7,8,9,10,11 present in the originally elected species has the following sequence:
MQIELSTCFFLCLLRFCFSATRRYYLGAVELSWDYMQSDLGELPVDARFPPRVPKSFPFNTSVVYKKTLFVEFTDHLFNIAKPRPPWMGLLGPTIQAEVYDTVVITLKNMASHPVSLHAVGVSYWKASEGAEYDDQTSQREKEDDKVFPGGSHTYVWQVLKENGPMASDPLCLTYSYLSHVDLVKDLNSGLIGALLVCREGSLAKEKTQTLHKFILLFAVFDEGKSWHSETKNSLMQDRDAASARAWPKMHTVNGYVNRSLPGLIGCHRKSVYWHVIGMGTTPEVHSIFLEGHTFLVRNHRQASLEISPITFLTAQTLLMDLGQFLLFCHISSHQHDGMEAYVKVDSCPEEPQLRMKNNEEAEDYDDDLTDSEMDVVRFDDDNSPSFIQIRSVAKKHPKTWVHYIAAEEEDWDYAPLVLAPDDRSYKSQYLNNGPQRIGRKYKKVRFMAYTDETFKTREAIQHESGILGPLLYGEVGDTLLIIFKNQASRPYNIYPHGITDVRPLYSRRLPKGVKHLKDFPILPGEIFKYKWTVTVEDGPTKSDPRCLTRYYSSFVNMERDLASGLIGPLLICYKESVDQRGNQIMSDKRNVILFSVFDENRSWYLTENIQRFLPNPAGVQLEDPEFQASNIMHSINGYVFDSLQLSVCLHEVAYWYILSIGAQTDFLSVFFSGYTFKHKMVYEDTLTLFPFSGETVFMSMENPGLWILGCHNSDFRNRGMTALLKVSSCDKNTGDYYEDSYEDISAYLLSKNNAIEPRSFSQNGAPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPASSPPVLKRHQAEITRTTLQSDQEEIDYDDTISVEMKKEDFDIYDEDENQSPRSFQKKTRHYFIAAVERLWDYGMSSSPHVLRNRAQSGSVPQFKKVVFQEFTDGSFTQPLYRGELNEHLGLLGPYIRAEVEDNIMVTFRNQASRPYSFYSSLISYEEDQRQGAEPRKNFVKPNETKTYFWKVQHHMAPTKDEFDCKAWAYFSDVDLEKDVHSGLIGPLLVCHTNTLNPAHGRQVTVQEFALFFTIFDETKSWYFTENMERNCRAPCNIQMEDPTFKENYRFHAINGYIMDTLPGLVMAQDQRIRWYLLSMGSNENIHSIHFSGHVFTVRKKEEYKMALYNLYPGVFETVEMLPSKAGIWRVECLIGEHLHAGMSTLFLVYSNKCQTPLGMASGHIRDFQITASGQYGQWAPKLARLHYSGSINAWSTKEPFSWIKVDLLAPMIIHGIKTQGARQKFSSLYISQFIIMYSLDGKKWQTYRGNSTGTLMVFFGNVDSSGIKHNIFNPPIIARYIRLHPTHYSIRSTLRMELMGCDLNSCSMPLGMESKAISDAQITASSYFTNMFATWSPSKARLHLQGRSNAWRPQVNNPKEWLQVDFQKTMKVTGVTTQGVKSLLTSMYVKEFLISSSQDGHQWTLFFQNGKVKVFQGNQDSFTPVVNSLDPPLLTRYLRIHPQSWVHQIALRMEVLGCEAQDLYDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
Amended claim 98, as filed 11/13/2025 now recites
….wherein the XTEN sequences comprise multiple units of non-overlapping sequences of a single motif family selected from the group consisting of SEO ID NOs: 49-78.
For purposes of applying prior art, this limitation is interpreted to mean that all XTEN “sequences” present must comprise multiple instances of at least one sequence from among SEQ ID NOs: 49-78. The usage of “single” may be deemed confusing in context, because the XTEN sequences recited belong to multiple “motif” families (e.g., SEQ ID NOs: 54-64 belong to two or more motif families as shown at Table 2A at pages 62-63 of the instant Specification). This is reasonable because it is not presumed that the Applicant excluded “AE” motif sequences (i.e., present in the originally elected species), which all simultaneously belong to two or three different motif families (see Spec. filed 7/25/2023 at Table 2A at 62-63). This issue is addressed under 35 USC 112(b), below.
Amended claim 98, as filed 11/13/2025 now recites
wherein the XTEN sequence is connected to (i) the VWF protein and the heterologous moiety, (ii) the heterologous moiety [[(H1)]]and the VWF linker, or (ii) the VWF linker and the VWF protein;
The “XTEN” referenced is inferred to necessarily be the XTEN present in the first polypeptide chain since all recitations at this portion require components of the first polypeptide chain, and therefore no lack of antecedent basis rejection has been made. The additional recitations of (i), (ii), and (ii), are understood to require direct XTEN placement between the N- and C-termini of the recited components without intermediate linkers between these domains. However, in a practical sense, this is not a meaningful distinction because the heterologous moiety, VWF linker, VWF protein, and XTEN sequence are all defined using open-ended terminology, meaning any intervening amino acids or peptide sequences can be arbitrarily deemed to be a portion of any of the enumerated components. At best, this amended language requires that the XTEN sequence of the first polypeptide chain be arranged, either N- to C- or C- to N-terminus, as (i) [VWF protein]-[XTEN]-[H1], (ii) [H1]-[XTEN]-[VWF linker], or (iii) [VWF linker]-[XTEN]-[VWF protein]. The originally elected species is understood to satisfy the general arrangement, N- to C-terminus, of [VWF protein]-[XTEN]-[VWF linker]-[H1].
Amended claim 98, as filed 11/13/2025 now recites
…wherein the first polypeptide chain and the second polypeptide chain are associated by a disulfide bond;
This limitation does not literally or implicitly appear in the originally filed disclosure commensurate in the context presently claimed. Rather, the only exemplification and discussion of this functional result in view of any explicitly described structure capable of yielding such outcome is found at ¶[0122] of the specification, and is limited to immunoglobulin constant regions, and specifically to Fc regions or “another FcRn binding partner” (see Spec. filed 7/25/2023 at ¶[0122]). Although a generic discussion is provided at ¶[0087], this disclosure merely discusses a hypothetical outcome in the absence of meaningful discussion of how such outcome may be achieved (see Spec. filed 7/25/2023 at ¶[0087]). For purposes of applying prior art, this limitation is deemed satisfied by embodiments comprising two heterologous regions, wherein both such regions each comprise an Fc region.
Additional claim interpretations are set forth below.
Withdrawn Claim Rejections
The rejections of claims 98 and 112-120 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite have been overcome in view of the Amendments and evidence regarding trademarks as filed 11/13/2025. However, such amendments have necessitated new rejections under 35 USC §112(b), which are set forth below.
The rejections of claims 117 and 119 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form, is withdrawn in view of the Amendments filed 11/13/2025. However, the amendments have raised new issues necessitating a new rejection under 35 USC § 112(d), as set forth below.
The rejections of claims 98 and 112-120 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, has been overcome by the amendments filed 11/13/2025. However, the amendments have raised new issues necessitating a new rejection under 35 USC § 112(a), as set forth below.
The rejection of claims 98 and 112-120 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, for lack of scope of enablement, has been overcome by the amendments filed 11/13/2025.
New Claim Rejections Necessitated by Applicant Amendment
Claim Rejections - 35 USC § 112(b)
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 98 and 112-120 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Amended claim 98, as filed 11/13/2025 now recites
….wherein the XTEN sequences comprise multiple units of non-overlapping sequences of a single motif family selected from the group consisting of SEO ID NOs: 49-78.
This phrase renders the claim scope indefinite because the phrase “single motif family” is inconsistent with the group “consisting of SEQ ID NOs: 49-78”, which are not limited to a “single motif family”. Rather, SEQ ID NO: 53 belongs to both the “AE” and “AM” motif family; SEQ ID NOs: 54-56 each belong to the “AE”, “AM”, and “AQ” motif families; and SEQ ID NOs: 57-60 each belong to the “AF” and “AM” families; SEQ ID NOs: 61-64 each belong to the “AG” and “AM” families (see, e.g., Spec. filed 7/25/2023 at Table 2A at 62-63). Accordingly, the claim scope is indefinite because it appears internally inconsistent since the recited sequences do not belong to a “single motif family”. Accordingly, it is unclear if this inconsistency should be interpreted (I) to exclude XTEN embodiments comprising SEQ ID NOs: 54-64 or having an “AE”, “AM”, “AF”, or “AM” motif since all such motifs and sequences are only identified as belonging to multiple motif families on record, which would exclude the originally elected species (see, e.g., Spec. filed 7/25/2023 at Table 2A at 62-63), or (II) if the claim scope includes any XTEN sequence comprising at least one sequence selected from the group consisting of SEQ ID NOs: 49-78. Accordingly, the amended claim language renders the claim scope indefinite. For purposes of applying prior art, claim 98 is understood consistent with (II) above, which includes the originally elected species. Applicant may overcome this rejection by, for example, amending claim 98 to recite
….wherein the XTEN sequences comprise one or more sequences selected from the group consisting of SEO ID NOs: 49-78.
Such amendments would clarify this issue.
Amended claim 98 as filed 11/13/2025, now recites and requires the following functional outcome
…wherein the first polypeptide chain and the second polypeptide chain are associated by a disulfide bond;
This renders the metes and bounds of the claim scope indefinite as follows: First, the added “wherein” clause does not actually appear in the originally filed disclosure in the claimed context and fails to correspond to a clear, unambiguous definition. Second, the newly added “wherein” clause raises multiple threshold questions, including “what structure is required to achieve the required outcome?”, and “how does this wherein clause structurally limit the compounds and active method steps recited in the claim?”. Third, it is unclear if the “wherein” clause excludes some heterologous moieties. Although “heterologous moieties” are defined as including multiple distinct structures (see, e.g., Spec. filed 7/25/2023 at ¶¶[0015]-[0016]), the only structure discussed on record in the context of disulfide bond formation is immunoglobulin constant regions, and specifically to Fc regions or “another FcRn binding partner” (see Spec. filed 7/25/2023 at ¶[0122]). Accordingly, it is unclear if the “wherein” clause is intended to exclude other heterologous moieties or not. In sum, it is unknown what structural limitations are required to achieve the functional outcome recited in the “wherein” clause as presently claimed. Per MPEP § 2173.05(g),
[T]he use of functional language in a claim may fail "to provide a clear-cut indication of the scope of the subject matter embraced by the claim" and thus be indefinite. In re Swinehart, 439 F.2d 210, 213 (CCPA 1971). For example, when claims merely recite a description of a problem to be solved or a function or result achieved by the invention, the boundaries of the claim scope may be unclear. Halliburton Energy Servs., Inc. v. M-I LLC, 514 F.3d 1244, 1255, 85 USPQ2d 1654, 1663 (Fed. Cir. 2008)
In addition, the Courts have stated
“[r]egardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to the subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods.” University of Rochester v. G.D. Searle Co., 69 USPQ2d 1886 1984 (CAFC 2004) (emphasis added).
This is pertinent because MPEP § 2173 notes that the “primary purpose of this requirement of definiteness of claim language is to ensure that the scope of the claims is clear so the public is informed of the boundaries of what constitutes infringement of the patent”. Here, it is unclear if the “wherein” clause requires two heterologous moieties to be present (i.e., one in each sequence), wherein both heterologous moieties are limited to immunoglobulin constant regions comprising an Fc region, or if the “wherein” clause limits the required structures in some other way. Accordingly, an artisan would not know the boundaries of what does or does not constitute infringement. For purposes of applying prior art, the “wherein” clause is understood to read upon at least embodiments wherein both peptides comprise a heterologous moiety, and wherein the heterologous region in both sequences corresponds to an Fc region (see Spec. filed 7/25/2023 at ¶[0122]). This is reasonable in view of the originally filed disclosure.
Claims 112-120 depend directly or indirectly upon indefinite claim 98, but fail to clarify the indefinite aspects of the base claim. Accordingly, claims 112-120 are rejected for the reasons applied to claim 98.
Claims 98 and 112-120 are rejected.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 113, 117, and 119 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claims 113, 117, and 119 depend from amended claim 98, which was amended to recite and require the following functional outcome
…wherein the first polypeptide chain and the second polypeptide chain are associated by a disulfide bond;
This limitation is not defined in the specification and does not appear in the context of amended claim 98 in the originally filed disclosure. For purposes of the instant rejection, this limitation is understood to require both sequences at amended claim 98 to comprise a heterologous moiety, and wherein the heterologous region in both sequences corresponds to an Fc region (see Spec. filed 7/25/2023 at ¶[0122]). Claim 113 recites only that the second polypeptide must comprise a second heterologous moiety, which is understood to be necessitated by the “wherein” clause of claim 98 as explained above, and therefore claim 113 fails to further limit the subject matter of the claim upon which it depends. Claims 117 and 119 are not limited to an Fc region, and zero implicit or inherent disclosures of record evidence that this functional limitation may be satisfied by a C-terminal peptide (CTP) of the β subunit of human chorionic gonadotropin. Accordingly, claims 117 and 119 are rejected for failing to include all the limitations of the claim upon which it depends. Therefore, claims 113, 117, and 119 are rejected.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 112(a), Written Description
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 98 and 112-120 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The applicable legal issues pertaining to the written description requirement of original claims is set forth at MPEP § 2163(II)(3)(a) and MPEP §2163.03(V).
Brief Statement of the Issue(s)
Following the amendments filed 11/13/2025, independent claim 98 recites the following functional outcome
…wherein the first polypeptide chain and the second polypeptide chain are associated by a disulfide bond;
However, it is unknown what structures are actually required to achieve this functional outcome, and therefore it is unknown how this “wherein” clause actually limits the structures recited within claim 98.
Claim Scope
Claim 98 is representative of the pending claim scope.
Actual Reduction to Practice
Prophetic examples are discussed generically in the specification (see, e.g., Spec. filed 7/25/2025 at ¶¶[0181]-[0211]); however, zero examples were reduced to practice showing, explaining, or exemplifying a method as claimed
…wherein the first polypeptide chain and the second polypeptide chain are associated by a disulfide bond;
Although at ¶[0183], the disclosure mentions disulfide bond formation, this is in the context of the VWF protein domains rather than between the first and second polypeptides as instantly claimed (i.e., the VWF protein is found only in the first polypeptide; see instant claims 98, 114-116); accordingly, this disclosure is not relevant to the “wherein” clause at claim 98.
Assessment of whether disclosed species are representative of the claimed genus
MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus (see, e.g., MPEP § 2163(II)(3)(a), MPEP §2163.03(V)). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. In this case, the claims encompasses an unknown but potentially infinitely large genus of methods requiring some, unknown, unspecified structures sufficient to achieve the functional outcome recited in the “wherein” clause of claim 98. However, as noted above, zero embodiments of the claimed invention were reduced to practice showing, explaining, or exemplifying the structural metes and bounds of embodiments included or excluded from the pending claim scope by the newly added “wherein” clause.
Although the MPEP does not define what constitutes a sufficient number of representative species, the Courts have indicated that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gostelli, 872 F.2d at 1012, 10 USPQ2d at 1618. Similarly, the disclosure of zero examples of the claimed subgenera, do not provide sufficient disclosure to satisfy the written description requirement for the instantly claimed invention.
Accordingly, the claims encompass a broad and highly varied genus of method utilizing >>>trillions of different methods utilizing various chemical structures, host cells, and unspecified steps suitable for achieving the “wherein” clause, including methods potentially utilizing undisclosed structures wherein the second polypeptide does not have a heterologous moiety, or structures wherein the heterologous moieties of both sequences are not required to comprise an Fc region. However, zero examples of such an invention was reduced to practice. Accordingly, the disclosure does not reasonably provide support for the full scope of the pending claims.
Identifying characteristics of the genus
In the absence of a reduction to practice of a representative number of species, the written description requirement for a claimed genus may be satisfied by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.
The “wherein” clause of claim 98 does not appear in the originally filed disclosure in the context of the pending claim scope.
The closest discussion and guidance on record appears at ¶¶[0087] and [0122]. The disclosure at ¶[0087] is limited to instances that are wholly generic in scope and lack any identification of structures and steps actually required to achieve disulfide bonds as claimed (see Spec. filed 7/25/2023 at ¶[0087]). Such disclosure is equivalent to an abstract idea of what the Applicant hopes to achieve, but fails to identify any specific structures required to actually achieve such outcomes commensurate in scope with the instant disclosure.
The disclosure at [0122] describes structural limitations wherein both sequences are required to comprise heterologous moieties, wherein the heterologous moiety in both sequences is required to comprise an Fc region (see Spec. filed 7/25/2023 at ¶[0122]). However, the instant claim is not limited to such embodiments as evidenced by dependent claims, and the “wherein” clause recited at claim 98 is not defined in a manner limiting the scope to only such embodiments.
Accordingly, in view of the specification, it is unclear what structures are included or excluded form the claim scope by the “wherein” clause added in the most recent reply. This is pertinent because the Courts have stated that
Regardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to the subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods.” University of Rochester v. G.D. Searle Co., 69 USPQ2d 1886 1984 (CAFC 2004) (emphasis added).
Accordingly, the originally filed disclosure fails to provide sufficient identifying characteristics of structures capable of achieving the functional outcome set forth in the newly added “wherein” clause, commensurate in scope with the pending claims, such that an artisan could reasonably differentiate, a priori, infringing and non-infringing embodiments.
US2011/0183907A112 reasonably informs artisans that disulfide bond formation relates to “correct folding” and can therefore impacts activity and can inform cell line choice (see, e.g., US’907 at ¶[0180]). Accordingly, in view of US’907, it is unclear if the “wherein” clause of instant claim 98 is meant to limit the host cells to particular eukaryotic cell lines (see id). The instant disclosure does not discuss cell line selection in the context of disulfide bond formation.
Neither the originally filed disclosure nor the prior art of record discusses disulfide bond formation within the context of the instant claim scope, in the absence of situations wherein both sequences comprise an Fc region (see Spec. filed 7/25/2023 at ¶[0122]).
Accordingly, no structure/function relationships known in the art or described in the originally filed disclosure pertaining the structural metes and bounds implied and required by the “wherein” clause has been identified on record.
Level of Skill and Predictability in the Art
Although the level of skill in the art is high, the predictability in the molecular biology arts is low due to the complexity of biological systems and biophysical interactions of peptide sequences in various arrangements and conformations. Specifically, an artisan would not be able to predict, a priori, and in the absence of any guidance, the minimal, common structures and cell lines required to satisfy the functional outcome of the “wherein” clause of claim 98 in view of the limited examples and guidance of record, which fail to provide a structure/function relationship delineating host cells, peptide sequences, and active method steps required or otherwise capable of achieving the functional outcome of the “wherein” clause commensurate in scope with the pending claims..
Accordingly, in the absence of sufficient structure/function teachings, an artisan would not reasonably conclude that Applicant possessed the full scope of the broad and highly varied genus of methods
Conclusion
The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does "little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate."). The courts have stated that “merely drawing a fence around a perceived genus is not a description of the genus. One needs to show that one has truly invented the genus, i.e., that one has conceived and described sufficient representative species encompassing the breadth of the genus. Otherwise, one has only a research plan, leaving it to others to explore the unknown contours of the claimed genus” (see, e.g., AbbVie v. Janssen, 111 USPQ2d 1780 (Fed. Cir. 2014) at 1789). Likewise, in the instant case, the Applicants have claimed a broad and highly varied genus potentially encompassing >>>trillions of species, but have failed to identify any common structure/function sufficient to reasonably inform an artisan of the metes and bounds of the claim scope as modified by the “wherein” clause added in the most recent Reply, such that the description evidences possession of the full scope of the claimed genera of methods as required by 35 USC 112, or to reasonably inform an artisan how to identify and distinguish among infringing methods and non-infringing methods since “XTEN” is not a structurally defined genus, but rather appears to be an abstract concept satisfied by an unknown number of sequences.
Notably, “[r]egardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to the subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods.” University of Rochester v. G.D. Searle Co., 69 USPQ2d 1886 1984 (CAFC 2004). Likewise, in the absence of clear identification of what structures are actually required to achieve the functional result recited in the “wherein” clause of claim 98, an artisan would not reasonably be aware of what did or did not constitute infringement a priori, and therefore “the inventor cannot lay claim to the subject matter” since the Specification fails to provide “a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods.”
In conclusion, for the reasons discussed above, the skilled artisan would not reasonably conclude that the inventor(s), at the time the application was filed, had possession of the full scope of the claimed invention, or that the description satisfied the requirements of 35 USC 112(a).
Accordingly, claims 98 and 112-120 are rejected.
Claim Rejections - 35 USC § 112(a), New Matter
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 98 and 112-120 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Lack of literal Support
The MPEP states that "[w]hile there is no in haec verba requirment, newly added claim limitations must be supported in the specification through express, implicit, or inherent disclosure." See MPEP 2163.
Amended claim 98 does not literally appear in the originally filed disclosure. Specifically, claim 98 was amended to recite the following functional outcome
…wherein the first polypeptide chain and the second polypeptide chain are associated by a disulfide bond;
This limitation is made in the context of a genus that does not recite nor require a second heterologous moiety or an Fc region to be present in both sequences. Accordingly, this language does not literally appear in the originally filed disclosure in the context of instant claim 98.
Accordingly, claim 98 does not literally appear in the originally filed disclosure.
Lack of Implicit or Inherent Support
The MPEP states that "[w]hile there is no in haec verba requirment, newly added claim limitations must be supported in the specification through express, implicit, or inherent disclosure." See MPEP 2163. As noted above, the claims are not literally or inherently supported by the originally filed disclosure. Accordingly, the relevant issue is whether or not the new amendments and resulting claim scope is implicitly or inherently supported by the originally filed disclosure.
Per MPEP § 2163(I)(B), “[a]n amendment to correct an obvious error does not constitute new matter where the ordinary artisan would not only recognize the existence of the error in the specification, but also recognize the appropriate correction. In re Oda, 443 F.2d 1200, 170 USPQ 268 (CCPA 1971)”. Here, no allegation that the amendments correct an obvious error has been made. Furthermore, upon inspection, Examiner is unable to identify any single “obvious error” that would lead to instantly amended claim 98 and the scope thereof. Accordingly, the amendments cannot be said to correct an “obvious error”, but instead the amendments attempt to circumvent the issue by narrowing the claim scope to a previously unclaimed genus.
The closest discussion and guidance on record appears at ¶¶[0087] and [0122]. However, these disclosures are not equivalent or synonymous in scope with the instant claim scope, and therefore cannot be said to provide inherent or implicit support for instant claim 98.
Regarding the disclosure at ¶[0087], this disclosure is limited to instances that are wholly generic in scope and lack any specific identification of any actual structures and steps actually required to achieve disulfide bonds as claimed (see Spec. filed 7/25/2023 at ¶[0087]). Furthermore, the pending claim scope is not synonymous or equivalent to the language of ¶[0087]. Rather, such disclosure is equivalent to an abstract idea of what the Applicant hopes to achieve, but fails to identify any specific structures required to actually achieve such outcomes commensurate in scope with the instant disclosure.
The disclosure at [0122] describes structural limitations wherein both sequences at claim 98 are required to comprise heterologous moieties (currently only one is required), wherein the heterologous moiety in both sequences is further required to comprise an Fc region (see Spec. filed 7/25/2023 at ¶[0122]). However, the instant claim is not limited to such embodiments as evidenced by dependent claims, and the “wherein” clause recited at claim 98 is not defined in a manner limiting the scope to only such embodiments. Accordingly, this limited disclosure does not provide inherent or implicit support commensurate in scope with the pending claims.
Conclusion
Per MPEP § 2163, new or amended claims which introduce elements or limitations which are not supported by the as-filed disclosure violate the written description requirement (see, e.g., In re Lukach, 442 F.2d 967, 169 USPQ 795 (CCPA 1971)). Here, the newly added claim limitations result in a narrower claim genus which defines a novel subgenus of species that was not inherently, implicitly, or literally supported by the originally filed disclosure.
Accordingly, claims 98 and 112-120 are rejected.
Revised Claim Rejections as Necessitated by Applicant Amendment
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 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.
Claims 98, 112-114, and 116-120 are rejected under 35 U.S.C. 103 as being unpatentable over US2011/0183907A113 in view of US2010/0239554A114 and Waugh et al15.
Claim interpretation: The applicable claim interpretation has been set forth in a preceding rejections and also in a separate section above, and those discussions and interpretations are incorporated into the instant rejection. Additional claim interpretations are set forth below.
Regarding instant claim 98 and a method of transfecting and expressing polypeptides comprising VWF and FVIII, US’907 teaches and claims polynucleotides encoding a complex comprising both a “modified FVIII” and a “modified VWF polypeptide” (see, e.g., US’907 at abs, ¶¶[0035], [0046]-[0048], [0178]-[0180], claims 2, 3(e), 16-18, 20-21), which may be utilized in methods of expressing such modified FVIII and modified VWF in host cells, such as HEK293 cells (see, e.g., US’907 at abs, ¶¶[0035], [0046]-[0048], [0180]). Regarding instant claim 98, 114, 116-118 and the substructure of [VWF protein]-[VWF Linker]-[H1], US’907 directs artisans to utilize modified VWF proteins having the structure
N-VWF-C-L1-H
wherein N is an N-terminal part of VWF, L1 is a chemical bond or linker sequence, H is a “HLEP”, and C is a C-terminal part of VWF (see, e.g., US’907 at ¶¶[0093]-[0098], [0145]-[0147]), and wherein one or more “HLEP”16 sequences may be utilized in tandem (see, e.g., US’907 at ¶[0101]). Regarding the presence of D1, D2, D3, and D’ domains of VWF, US’907 directs artisans to utilize various VWF sequences, including full-length VWF, which would necessarily encompass such domains (compare US’907 at ¶¶[0110]-[0112] with instant claims 98, 114 and 116). Regarding a [VWF Linker] that comprises a thrombin cleavage site (i.e., XVPR, wherein X is an aliphatic residue), US’907 explicitly identifies that the L1 linker may be a cleavable linker, and may specifically encompass “thrombin cleavage sites” (see, e.g., US’907 at ¶¶[0145]-[0147]; compare id. with instant claim 98). Regarding an [H1] heterologous moiety comprising an “immunoglobulin constant region or a portion thereof”, US’907 identifies that H may be a “HLEP” domain, and explicitly identifies that the “HLEP” includes Immunoglobulin constant regions (Fc) (see, e.g., US’907 at ¶¶[0160]-[0161]; compare id. with instant claims 117-118). In summary, US’907 reasonably directs artisans to make and use modified VWF proteins of form
[VWF]-[Linker with thrombin cleavage site]-[HLEP]0-1-[Fc]-[HLEP]0-1
wherein [HLEP]0-1 represents optional, additional Half-life Enhancing polypeptides that may be utilized in tandem (see, e.g., US’907 at ¶[0101]). Regarding instant claim 98, 113, 119-120, and the substructure of [FVIII]-[H2], US’907 directs artisans to utilize modified VWF proteins having the structure
N-FVIII-C-L1-H
wherein N is an N-terminal part of FVIII, L1 is a chemical bond or linker sequence, H is a “HLEP”, and C is a C-terminal part of FVIII (see, e.g., US’907 at ¶¶[0087]-[0092], [0145]-[0147]), and wherein one or more “HLEP” sequences may be utilized in tandem (see, e.g., US’907 at ¶[0101]). Regarding the presence of a “second heterologous moiety (H2)”, US’907 identifies that H may be a “HLEP” domain, and explicitly identifies that the “HLEP” includes Immunoglobulin constant regions (Fc) (see, e.g., US’907 at ¶¶[0160]-[0161]; compare id. with instant claims 113, 119-120). In summary, US’907 reasonably directs artisans to make and use modified FVIII proteins of form
[FVIII]-[L1]-[HLEP]0-1-[Fc]-[HLEP]0-1
wherein [HLEP]0-1 represents optional, additional Half-life Enhancing polypeptides that may be utilized in tandem (see, e.g., US’907 at ¶[0101]). Regarding amended claim 98 and the “wherein” clause requiring …wherein the first polypeptide chain and the second polypeptide chain are associated by a disulfide bond, this limitation has been rejected as indefinite, lacking written description, and constituting new matter. For purposes of the instant rejection, in view of the originally filed disclosure, it is reasonably inferred that the limitation is satisfied by at least any embodiment wherein both sequences comprise an [Fc] domain, which is reasonable in view of the originally filed disclosure (see Spec. filed 7/25/2023 at ¶[0122]). Here, the prior art teaches artisans to make and use modified VWF proteins of form
[VWF]-[Linker with thrombin cleavage site]-[HLEP]0-1-[Fc]-[HLEP]0-1
And directs artisans to reasonably directs artisans to make and use modified FVIII proteins of form
[FVIII]-[L1]-[HLEP]0-1-[Fc]-[HLEP]0-1
(see discussions above). Accordingly, such embodiments clearly encompass modified FVIII proteins and VWF proteins, wherein both have [Fc] regions. Accordingly, such structure is understood to necessarily satisfy the functional results required by the “wherein” clause of amended claim 98 since the regions would be capable of forming a disulfide bond upon expression (see, e.g., US’907 at abs, ¶¶[0035], [0046]-[0048], [0178]-[0180], claims 2, 3(e), 16-18, 20-21).
The primary reference differs from the instantly claimed invention as follows: US’907 does not teach or identify that the complexes of modified VWF and modified FVIII comprise XTEN sequences as instantly claimed.
XTEN was a prior art element: US’554 evidences that “XTEN” sequences were prior art elements (see, e.g., US’554 at title, abs, claims), which could be conjugated to biologically active proteins (“BP”), including coagulation proteins, in order to predictably and expectedly “enhance pharmacokinetic properties”, including terminal half-life of the BP (see, e.g., US’554 at claims 4-7, 12). US’554 informs artisans that such XTENylated fusion proteins could be encoded by polynucleotides and utilized in expression constructs within host cells (see, e.g., US’554 at claims 7, 22-30). The XTEN sequences exemplified include “AE288” (see, e.g., US’554 at SEQ ID NO: 206, Table 2 at ¶[0160]), which is identical to instant SEQ ID NO: 43 (compare id. with instant SEQ ID NO: 43, showing 100% sequence identity).
Regarding the thrombin cleavage site comprising X-V-P-R as required by claim 98, US’907 directs artisans to utilize linkers comprising thrombin cleavable motifs but does not disclose the thrombin cleavage sequence of LVPR. However, thrombin cleavage sequences were well known in the prior art as established by Waugh. Waugh identifies that the art-recognized thrombin cleavage sequence was understood to be LVPRGS, wherein cleavage occurs between R and G (see, e.g., Waugh at Table 1 on 284).
In sum, in view of the teachings of US’907 in view of US’554 and Waugh, an artisan would readily appreciate that XTEN sequences as disclosed by US’554 would be readily considered a “a “Half-life Enhancing Polypeptide” or “HLEP” as discussed by US’907 (see, e.g., US’907 at ¶¶[0149]-[0150]). Accordingly, an artisan would readily appreciate that XTEN sequences could be combined or simply substituted into the US’907 sequences to predictably and expectedly yield methods of transfecting host cells and expressing polypeptides comprising sequences such as
[VWF]-[Linker with thrombin cleavage site]-[XTEN AE288]0-1-[Fc]-[XTEN AE288]0-1
and
[FVIII]-[L1]-[ XTEN AE288]0-1-[Fc]-[ XTEN AE288]0-1
Wherein such sequences would be predicted and expected to exhibit the benefits ascribed to XTENylation in US’554, including “enhanced pharmacokinetic properties” such as improved terminal half-life relative to sequences lacking XTENylation.
Therefore, it would have been obvious to one of ordinary skill in the art, either before the effective filing date of the claimed invention (AIA ) or otherwise at the time the invention was made (pre-AIA ), to arrive at the instantly claimed invention in view of the prior art for at least the following reason(s):
First, the claimed invention is the obvious combination of prior art elements (i.e., polynucleotide sequences comprising modified VWF and modified FVIII as taught by US’907, and the XTEN sequences of US’554), according to known methods of co-expressing modified forms of VWF and FVIII in a host cell, wherein the modification includes one or more Half-life Enhancing polypeptides (HLEP) domains, to yield predictable results, namely the exact results taught and disclosed by US’907, but wherein the additional XTEN moiety would provide the advantageous additional results taught and suggested by US’554 (i.e., enhanced pharmacokinetic properties, improved half-life), and wherein the expressed proteins would be predictably usable in the applications taught, disclosed and suggested by US’907 (see, e.g., MPEP § 2143(I)(A), (G)). Furthermore, each element merely performs its art-recognized function in combination as it does separately.
Second, the claimed invention is the simple substitution of one known half-life extending moiety for another to obtain predictable results (i.e., the substitution of a polynucleotide encoding XTEN as taught by US’554 in place of a second HLEP domain in a modified VWF and FVIII expression system as taught by polynucleotide sequences comprising modified VWF and modified FVIII as taught by US’907), wherein the simple substitution would predictably and expectedly yield methods of transfecting host cells and expressing polypeptides comprising sequences such as
[VWF]-[Linker with thrombin cleavage site]-[XTEN AE288]0-1-[Fc]-[XTEN AE288]0-1
and
[FVIII]-[L1]-[ XTEN AE288]0-1-[Fc]-[ XTEN AE288]0-1
wherein such sequences would be predicted and expected to exhibit the benefits ascribed to XTENylation in US’554, including “enhanced pharmacokinetic properties” such as improved terminal half-life relative to sequences lacking XTENylation, while continuing to provide the benefits identified by the primary reference (i.e., modified VWF and FVIII proteins with improved half-lives, usable in therapeutic applications) (see, e.g., MPEP § 2143(I)(B), (D), (G)).
Furthermore, each element merely performs its art-recognized function in combination as it does separately.
Furthermore, there would be a reasonable expectation of success because the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)). Furthermore, it is well within the ordinary skill in the art to modify known sequences in a known manner and by using only known methods of conjugating known sequences having known benefits in order to obtain a conjugate sequence having the exact known, and expected benefits taught by the prior art. No evidence of unexpected results commensurate in scope with the requirements of MPEP §§ 716, 716.01, and 716.02 have been placed on record to date.
Accordingly, claims 98, 112-114, and 116-120 are rejected.
Claim 115 is rejected under 35 U.S.C. 103 as being unpatentable over US2011/0183907A117 in view of US2010/0239554A118 and Waugh et al19 as applied to claims 98, 112-114, and 116-120 above, and further in view of WO2013/083858 (June 13, 2013; cited in IDS filed 12/22/2023 as cite No. 199)
Claim Interpretation: The Applicable claim interpretation has been set forth above or has been set forth in previous rejections, and is incorporated herein. Additional claim interpretations are provided below.
The teachings of US’907 in view of US’554 and Waugh as applied to claims 98, 112-114, and 116-120, has been discussed above, and those teachings are incorporated into the instant rejection.
US’907 in view of US’554 and Waugh differ from instant claim 115 as follows: US’907 in view of US’554 and Waugh do not explicitly direct artisans to mutate the cysteine residues at positions 1099 and 1142 of instant SEQ ID NO: 2 (i.e., VWF).
WO’858 identifies that Cys1099 and/or Cys1142 could be advantageously mutated in VWF proteins and fragments, wherein such mutations would be predicted to reduce oligomerization/dimerization of VWF proteins, and thereby lead to a simpler product purification procedure from protein expression systems relative to unmodified proteins (see, e.g., WO’858 at 12 at lines 10-17, p 12-13 at bridging paragraph, p. 27 at embodiments 6-9, claims 10-12).
Therefore, it would have been obvious to one of ordinary skill in the art, either before the effective filing date of the claimed invention (AIA ) or otherwise at the time the invention was made (pre-AIA ), to arrive at the instantly claimed invention in view of the prior art for at least the following reason(s): The claimed invention of instant claim 115 is the obvious application of a known technique of mutating Cys1099 and/or Cys1142 in VWF as disclosed by WO’858 to the method of producing modified VWF and FVIII complexes via host expression systems as taught and suggested I view of US’907 in view of US’554 and Waugh, wherein the application of the known technique would improve purification and production of proteins in known and predictable ways as suggested by WO’858, namely the mutations would reduce oligomerization/dimerization of VWF proteins, and thereby lead to a simpler product purification procedure (see, e.g., MPEP § 2143(I)(C), (D), (F), (G)).
Furthermore, there would be a reasonable expectation of success because the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)). Furthermore, it is well within the ordinary skill in the art to modify known sequences in a known manner expressly taught and suggested by the prior art, in order to predictably and expectedly obtain the exact benefits ascribed to such modifications in the prior art. No evidence of unexpected results commensurate in scope with the requirements of MPEP §§ 716, 716.01, and 716.02 have been placed on record to date.
Accordingly, claim 115 is rejected.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP §§ 706.02(l)(1) - 706.02(l)(3) for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
[NSDP Rejection 01]
Claims 98 and 112-120 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-36 of U.S. Patent No. 10,138,29120 (Chhabra et al., Nov. 27, 2018; corresponding to US Application 14/413,765) in view of US2011/0183907A121.
Claim Interpretation: The Applicable claim interpretation has been set forth above or has been set forth in previous rejections, and is incorporated herein. Additional claim interpretations are provided below.
Although the claims at issue are not identical, they are not patentably distinct from each other in view of the prior art, as explained below.
Regarding the encoded chimeric polypeptides as tissue in instant claims 98 and 112-120, the structural requirements of the encoded peptides at issue in the pending claims and the polypeptides encompassed by the issued claims of US’291 substantially overlap in scope. Specifically, each claim set pertains to chimeric proteins comprising a first polypeptide comprising [VWF protein]-[XTEN]-[VWF linker22]-[First Fc region], and a second polypeptide comprising [FVIII protein]-[XTEN]-[Second Fc region] (compare instant claims 98 and 112-120 with US’291 at claims 1-36, especially claims 1, 9, 11, 14, and 29-31; note that US’291 refers to the “VWF linker” as a “thrombin cleavable linker”). The overlapping structure is readily apparent by simply comparing the originally elected species in the instant Application (i.e., a first polynucleotide corresponding to VWF-034 (SEQ ID NO: 92) and a second polynucleotide corresponding to FVIII169 (SEQ ID NO: 88)) with the structures set forth in the issued claims of US’291 (compare instant SEQ ID NO: 92 with US’291 at SEQ ID NO: 119 as recited at claims 6, 10-11, 20-21, and 33-36, showing 100% sequence identity; compare instant SEQ ID NO: 88 with US’291 at SEQ ID NO: 103 as recited at claims 6, 17-21, and 33-36, showing 100% sequence identity; compare instant SEQ ID NO: 43 with US’291 at SEQ ID NO: 39, showing 100% identity). Accordingly, all polypeptide based structural limitations (e.g., domains, heterologous moieties, cleavage sequences, etc.) at instant claims 98 and 112-120 overlap in scope with the issued claims of US’291, and therefore do not patentably distinguish the issued claim scope from the instant claim scope. Regarding amended claim 98 and the “wherein” clause requiring …wherein the first polypeptide chain and the second polypeptide chain are associated by a disulfide bond, this limitation has been rejected as indefinite, lacking written description, and constituting new matter. For purposes of the instant rejection, in view of the originally filed disclosure, it is reasonably inferred that the limitation is satisfied by at least any embodiment wherein both sequences comprise an [Fc] domain, which is reasonable in view of the originally filed disclosure (see Spec. filed 7/25/2023 at ¶[0122]). As noted above, the issued patent claims the same structures present in the originally elected species of the instant Application, and therefore such structures are reasonably inferred to necessarily satisfy the structures implied by the newly added “wherein” clause (see also US’291 at Fig. 6, showing Fc regions forming disulfide bonds, col 2-3 at bridging ¶, col 14 at lines 4-11, col. 23 at lines 1-10, col 26 at lines 60-66, col. 28 at lines 10-15; see, e.g., MPEP § 804(II)(B)(1), “those portions of the specification which provide support for the reference claims may also be examined and considered when addressing the issue of whether a claim in the application defines an obvious variation of an invention claimed in the reference patent or application”). In addition, claim 31 of US’291 explicitly identifies and claims that “the first Fc region and the second Fc region form a disulfide bond”.
The scope of the issued claims differ from the instant claim scope as follows: The instant claims are directed to a method of making the claimed peptides by transfecting a host cell with polynucleotides encoding the polypeptides, and expressing such polypeptides within a host cell. However, such difference is routine in the prior art as established in view of US’907 below.
Regarding instant claim 98 and a method of transfecting and expressing polypeptides comprising modified forms of VWF and FVIII, US’907 teaches and claims polynucleotides encoding a complex comprising both a “modified FVIII” and a “modified VWF polypeptide” (see, e.g., US’907 at abs, ¶¶[0035], [0046]-[0048], [0178]-[0180], claims 2, 3(e), 16-18, 20-21), which may be utilized in methods of expressing such modified FVIII and modified VWF in host cells, such as HEK293 cells (see, e.g., US’907 at abs, ¶¶[0035], [0046]-[0048], [0180]). Furthermore, the “modification” is understood to be one or more Half-life Enhancing polypeptides (“HLEP”) that may be utilized in tandem (see, e.g., US’907 at ¶[0101]), which may include Immunoglobulin constant regions (Fc) (see, e.g., US’907 at ¶¶[0160]-[0161]; compare id. with instant claims 113, 119-120), and other half-life extending moieties known in the prior art. Accordingly, the general method of transfecting host cells and expressing a complex comprising modified forms of VWF and FVIII were well known in the prior art.
Obviousness analysis: Under an obviousness analysis (see, e.g., MPEP § 804(II)(B)(3)), it is noted that the scope and content of the patent claim relative to the application claims at issue have been discussed above (see, e.g., MPEP § 804(II)(B)(3)(A)), and that the differences are that the instant claims attempt to make the exact same polypeptides recited and encompassed in the issued claims using a known, and routine method of transfecting host cells with polynucleotides encoding the same polypeptides, and expressing those polypeptides in the host cell (see discussion above regarding US’907). Accordingly, such applications and methods would have been readily obvious to an artisan in view of the issued claims because the difference in claim scope is the application of known expression systems in known host cells to produce the same predicted and expected outcome taught in view of US’907 (see, e.g., MPEP § 804(II)(B)(3)(B)). Accordingly, the present claims are directed to obvious variants of the issued claims because it is well-within the ordinary skill in the art to make polynucleotides encoding known polypeptides, transfect known host cells, and express the known polypeptides in a known expression system intended for that exact purpose (see, e.g., MPEP § 804(II)(B)(3)(C)-(D); see also MPEP §§ 2143(I)(A), (B), (C), (D), and (F), noting that simple substitution or combination of the issued polypeptides into the methods of the prior art of US’907 would predictably yield the pending claim scope; in addition or alternatively, see MPEP §§ 2143(I)(E), noting that there are a finite number of ways to produce peptides, namely manual synthesis methods and genetic expression routes, and therefore selecting one of two possibilities is obvious).
As issued claims in a U.S. patent, the reference claims are presumed to satisfy all statutory requirements in the absence of evidence to the contrary. Accordingly, the instant claims are directed to an obvious variation of the issued claims, namely the instant claims are directed to a method of making the polypeptides set forth in the issued claims using a routine and well-established methodology (i.e., transfection and expression in a host cell). Therefore, the instant claims are not patentably distinct from the issued claims.
As required at (C) of MPEP § 804(II), the rejection is not prohibited by 35 U.S.C. 121.
Accordingly, instant claims 98 and 112-120 are rejected.
[NSDP Rejection 02]
Claims 98 and 112-120 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 1109153423 (Chhabra et al., Aug. 17, 2021; corresponding to US Application 16/154,310).
Claim Interpretation: The Applicable claim interpretation has been set forth above or has been set forth in previous rejections, and is incorporated herein. Additional claim interpretations are provided below.
Regarding the encoded chimeric polypeptides as tissue in instant claims 98 and 112-120, US’534 claims a set of polynucleotides, and a host cell such as HEK293 cells “comprising the set of polynucleotides” (i.e., post-transfection) (see, e.g., US’534 at claims 1 and 3-5, 8-9, 11). Regarding the structural requirements of the encoded peptides at issue in the pending claims and the polypeptides encompassed by the issued claims of US’534 substantially overlap in scope, which is evidenced by simply comparing the originally elected species in the instant Application (i.e., a first polynucleotide corresponding to VWF-034 (SEQ ID NO: 92) and a second polynucleotide corresponding to FVIII169 (SEQ ID NO: 88)) with the recited structures set forth in the issued claims of US’534 (compare instant SEQ ID NO: 92 with US’534 at SEQ ID NO: 119 as recited at claims 16, 18, and 19, showing 100% sequence identity; compare instant SEQ ID NO: 88 with US’534 at SEQ ID NO: 103 as recited at claims 17 and 20, showing 100% sequence identity). Accordingly, all polypeptide-based structural limitations (e.g., domains, heterologous moieties, cleavage sequences, etc.) at instant claims 98 and 112-120 overlap in scope with the issued claims of US’291, and therefore do not patentably distinguish the issued claim scope from the instant claim scope. Regarding amended claim 98 and the “wherein” clause requiring …wherein the first polypeptide chain and the second polypeptide chain are associated by a disulfide bond, this limitation has been rejected as indefinite, lacking written description, and constituting new matter. For purposes of the instant rejection, in view of the originally filed disclosure, it is reasonably inferred that the limitation is satisfied by at least any embodiment wherein both sequences comprise an [Fc] domain, which is reasonable in view of the originally filed disclosure (see Spec. filed 7/25/2023 at ¶[0122]). As noted above, the issued patent claims the same structures present in the originally elected species of the instant Application, and therefore such structures are reasonably inferred to necessarily satisfy the structures implied by the newly added “wherein” clause (id.). Furthermore, an artisan would readily appreciate that an Fc-Fc disulfide bond between sequences is an obvious variant that would either necessarily or inherently form upon expression in a host cell (see, e.g., US’534 at col. 96-97 at bridging ¶; see, e.g., MPEP § 804(II)(B)(1), “those portions of the specification which provide support for the reference claims may also be examined and considered when addressing the issue of whether a claim in the application defines an obvious variation of an invention claimed in the reference patent or application”).
The claim scope of US’534 differs from the instantly pending claims as follows: Although US’534 recites products such as (i) a set of polynucleotides (see, e.g., claims 1-2, 12-20), and (ii) a host cell “stably transfected” with the polynucleotides (see, e.g., claims 8-11), the instant claims are directed to methods of making a “stably transfected” host cell, transfected with the same polynucleotides and capable of expressing the polypeptides encoded therein.
Accordingly, the difference between the issued and pending claims appear to be very minor, because the issued claim set recites and claims products that are intermediates in the methods presently claimed (i.e., a stably transfected HEK293 host cell, transfected with the identical set of polynucleotides is claimed in issued claims 8-11, but is also required in the originally elected species in the instant application). Therefore, the answer to the question “is any invention claimed . . . an obvious variation of[] an invention claimed in the patent”24
is clearly “yes”. The relationship between polynucleotides and polypeptides is well-established, and one of ordinary skill in the art readily appreciates how to utilize polynucleotides that encode a desired and known polypeptide. Likewise, an artisan can readily identify whether or not a particular polynucleotide sequence is capable of encoding a desired polypeptide in a particular organism. Furthermore, a host cell “stably transfected” with the polynucleotides (see, e.g., claims 8-11), would be readily expected to express the polypeptides encoded by the polynucleotides, and therefore the product as claimed implicitly or inherently satisfies the active method explicitly required by the instant claims.
Anticipation analysis: MPEP § 804(II)(B)(2)-(3) further identify that a Nonstatutory Double Patenting Rejection may be appropriate based upon either an anticipation analysis or an obviousness analysis (see, e.g., MPEP § 804(II)(B)(2)-(3)). Here, it is the Examiner’s position that under an anticipation analysis an artisan would at once envisage the instantly claimed methods in view of the explicitly recited products set forth in the issued claims (i.e., stably transfected host cells, transfected with the same polynucleotides, wherein the stably transfected host cell would implicitly or inherently express the same polypeptides) (see, e.g., MPEP § 804(II)(B)(2)).
Obviousness analysis: Under an obviousness analysis (see, e.g., MPEP § 804(II)(B)(3)), it is noted that the scope and content of the patent claim relative to the application claims at issue have been discussed above (see, e.g., MPEP § 804(II)(B)(3)(A)), and that the differences are that the instant claims attempt to claim a method that would necessarily form a stably transfected host cell capable of expressing polypeptides, which is understood to be a product explicitly claimed and recited by the issued claims; accordingly the claims at issue are directed to different, but substantially and materially overlapping subject matter, such that the instantly claimed method would be at once envisaged and understood to be required to make and use the products claimed and set forth in the issued patent (see, e.g., MPEP § 804(II)(B)(3)(B)). Accordingly, the present claims are directed to obvious variants of the representative claims because it is well-within the ordinary skill in the art to produce polypeptides from stably transfected host cells transfected with a set of polynucleotides encoding desired polypeptides (see, e.g., MPEP § 804(II)(B)(3)(C)-(D); see also MPEP §§ see also MPEP §§ 2143(I)(A), (B), (C), (D), and (F)).
As issued claims in a U.S. patent, the reference claims are presumed to satisfy all statutory requirements in the absence of evidence to the contrary. Accordingly, the instant claims are directed to an obvious variation of the issued claims, namely the instant claims are directed to a method of making polypeptides encoded by and necessarily expressed by the stably transfected host cells recited and claimed in the issued claim set. Therefore, the instant claims are not patentably distinct from the issued claims.
As required at (C) of MPEP § 804(II), the rejection is not prohibited by 35 U.S.C. 121.
Accordingly, instant claims 98 and 112-120 are rejected.
[NSDP Rejection 03]
Claims 98, and 112-120 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-58 of U.S. Patent No. 11,192,93625 (Chhabra et al., Dec. 7, 2021; corresponding to US Application 15/110,673) in view of US2011/0183907A126.
Claim Interpretation: The Applicable claim interpretation has been set forth above or has been set forth in previous rejections, and is incorporated herein. Additional claim interpretations are provided below.
Although the claims at issue are not identical, they are not patentably distinct from each other because they are reasonably understood to substantially overlap in scope. Regarding the encoded chimeric polypeptides as tissue in instant claims 98 and 112-120, the structural requirements of the encoded peptides at issue in the pending claims and the polypeptides encompassed by the issued claims of US’936 substantially overlap in scope. Specifically, each claim set pertains to chimeric proteins comprising a first polypeptide comprising [VWF protein]-[XTEN]-[VWF linker27]-[First Fc region], and a second polypeptide comprising [FVIII protein]-[XTEN]-[Second Fc region] (compare instant claims 98 and 112-120 with US’936 at claims 1-58, especially claims 1, 7, 19, 21, 24, 30, 32, and 44). Specifically, regarding the VWF-comprising polypeptide, US’936 teaches and encompasses polypeptides sharing 90% sequence identity with SEQ ID NO: 197 (i.e., VWF059) (see, e.g., US’936 at claims 1 and 19), which is reasonably understood to include the exemplified sequence of SEQ ID NO: 152 (i.e., VWF057; which shares 98.06% sequence identity with SEQ ID NO: 197), which comprises an
XTEN sequence (compare US’936 at VWF057, SEQ ID NO: 152, Fig. 9, col. 13 at lines 20-40 with instant claims 98, 112);
Fc domain (compare US’936 at VWF057, SEQ ID NO: 152, Fig. 9, col. 13 at lines 20-40 with instant claims 98, 117-118);
VWF linker comprising LVPR (compare US’936 at VWF057, SEQ ID NO: 152, Fig. 9, col. 13 at lines 20-40 with instant claims 98);
D’D3 domains (compare US’936 at VWF057, SEQ ID NO: 152, Fig. 9, col. 13 at lines 20-40 with instant claims 98, 114); and
mutations at the positions corresponding to residues 1099 and 1142 of instant SEQ ID NO: 2 (compare US’936 at VWF057, SEQ ID NO: 152, Fig. 9, col. 13 at lines 20-40 with instant claims 98, 115, noting C33A and C379A mutations).
Regarding instant claim 116 and the presence of the D1 and D2 domains of VWF, US’936 identifies explicitly that the disclosed embodiments, which would include SEQ ID NO: 152, may comprise the D1 and D2 domains of VWF (see, e.g., US’936 at claims 1, 16-17, and 19). Accordingly, the scope of the VWF-containing polypeptides substantially and materially overlap in scope between both applications. Regarding the FVIII-containing component, US’936 claims a polypeptide chain comprising a FVIII protein, an XTEN sequence, and a immunoglobulin constant Fc region (see, e.g., US’936 at claims 1, 4, 7-8, 12-14, 21-22, 24; compare id. with instant claims 98, 113, 119 and 120). Regarding amended claim 98 and the “wherein” clause requiring …wherein the first polypeptide chain and the second polypeptide chain are associated by a disulfide bond, this limitation has been rejected as indefinite, lacking written description, and constituting new matter. For purposes of the instant rejection, in view of the originally filed disclosure, it is reasonably inferred that the limitation is satisfied by at least any embodiment wherein both sequences comprise an [Fc] domain, which is reasonable in view of the originally filed disclosure (see Spec. filed 7/25/2023 at ¶[0122]). Here, US’936 explicitly claims that the Fc-Fc domains interact via a disulfide bond (see, e.g., US’936 at claims 1, 3, 6, 14, 21, 23-25, 34, and 44). In sum, the primary reference claims chimeric proteins that substantially and materially overlap in scope with the polypeptide structures recited in the instant claims; therefore the recitation of such structural limitations do not patentably distinguish the issued claim scope from the instant claim scope.
The scope of the issued claims differ from the instant claim scope as follows: The instant claims are directed to a method of making the peptides as claimed by US’936 by transfecting a host cell with polynucleotides encoding the polypeptides, and expressing such polypeptides within a host cell. However, such difference is routine in the prior art as established in view of US’907 below, because in view of the claimed peptides of the primary reference, an artisan would at once envisage routine methods of making such polypeptides.
Regarding instant claim 98 and a method of transfecting and expressing polypeptides comprising modified forms of VWF and FVIII, US’907 teaches and claims polynucleotides encoding a complex comprising both a “modified FVIII” and a “modified VWF polypeptide” (see, e.g., US’907 at abs, ¶¶[0035], [0046]-[0048], [0178]-[0180], claims 2, 3(e), 16-18, 20-21), which may be utilized in methods of expressing such modified FVIII and modified VWF in host cells, such as HEK293 cells (see, e.g., US’907 at abs, ¶¶[0035], [0046]-[0048], [0180]). Furthermore, the “modification” is understood to be one or more Half-life Enhancing polypeptides (“HLEP”) that may be utilized in tandem (see, e.g., US’907 at ¶[0101]), which may include Immunoglobulin constant regions (Fc) (see, e.g., US’907 at ¶¶[0160]-[0161]; compare id. with instant claims 113, 119-120), and other half-life extending moieties known in the prior art. Accordingly, the general method of transfecting host cells and expressing a complex comprising modified forms of VWF and FVIII were well known in the prior art.
Obviousness analysis: Under an obviousness analysis (see, e.g., MPEP § 804(II)(B)(3)), it is noted that the scope and content of the patent claim relative to the application claims at issue have been discussed above (see, e.g., MPEP § 804(II)(B)(3)(A)), and that the differences are that the instant claims attempt to make the exact same polypeptides recited and encompassed in the issued claims using a known, and routine method of transfecting host cells with polynucleotides encoding the same polypeptides, and expressing those polypeptides in the host cell (see discussion above regarding US’907). Accordingly, such applications and methods would have been readily obvious to an artisan in view of the issued claims because the difference in claim scope is the application of known expression systems in known host cells to produce the same predicted and expected outcome taught in view of US’907 (see, e.g., MPEP § 804(II)(B)(3)(B)). Accordingly, the present claims are directed to obvious variants of the issued claims because it is well-within the ordinary skill in the art to simply ask and ascertain “how do I make the claimed peptides?” and then at once envisage routine methods of making polynucleotides encoding known polypeptides, transfecting known host cells, and expressing the known polypeptides in a known expression system intended for the exact purpose of expressing polypeptides (see, e.g., MPEP § 804(II)(B)(3)(C)-(D); see also MPEP §§ 2143(I)(A), (B), (C), (D), and (F), noting that simple substitution or combination of the issued polypeptides into the methods of the prior art of US’907 would predictably yield the pending claim scope; in addition or alternatively, see MPEP §§ 2143(I)(E), noting that there are a finite number of ways to produce peptides, namely manual synthesis methods and genetic expression routes, and therefore selecting one of two possibilities is obvious).
As issued claims in a U.S. patent, the reference claims are presumed to satisfy all statutory requirements in the absence of evidence to the contrary. Accordingly, the instant claims are directed to an obvious variation of the issued claims, namely the instant claims are directed to a method of making the polypeptides set forth in the issued claims using a routine and well-established methodology (i.e., transfection and expression in a host cell). Therefore, the instant claims are not patentably distinct from the issued claims.
As required at (C) of MPEP § 804(II), the rejection is not prohibited by 35 U.S.C. 121.
Accordingly, instant claims 98 and 112-120 are rejected.
Response to Arguments
Applicant’s arguments with respect to the pending claims have been fully considered but are substantially rendered moot in view of the new or revised grounds of rejection, as set forth above and necessitated by Applicant amendment. Remaining applicable arguments have been fully considered but not found persuasive as explained below.
It is the Examiner’s understanding that Applicant addresses the rejection under 35 USC 103 in view of Weimer, Schellenberger, and Waugh at pages 9-10 (see, e.g., Reply filed 11/13/2025 at 9 at § “35 U.S.C. § 103” to page. 10 at 1st partial ¶). It is the Examiner’s understanding that Applicant raises two issues: (i) that the references, considered individually, do not render the claims obvious; and (ii) that the references do not satisfy the newly added “wherein” clause requiring a covalent disulfide bond (see id). Regarding (i), in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Regarding (ii), the “wherein” clause at issue has been rejected as indefinite, lacking written description support, and constituting new matter, and therefore Applicant’s reliance upon this limitation is misplaced. As explained in the revised rejection, the prior art teaches claims polynucleotides encoding a complex comprising both a “modified FVIII” and a “modified VWF polypeptide” (see, e.g., US’907 at abs, ¶¶[0035], [0046]-[0048], [0178]-[0180], claims 2, 3(e), 16-18, 20-21), which may be utilized in methods of expressing such modified FVIII and modified VWF in host cells, such as HEK293 cells (see, e.g., US’907 at abs, ¶¶[0035], [0046]-[0048], [0180]). Critically, the “modified FVIII” and “modified VWF polypeptide” may each comprise an [Fc] domain as explained in the rejection. Examiner notes that Applicant does not dispute that the prior art teaches such polypeptides, that the prior art renders obvious methods of expressing such polypeptides in host cells, or that such sequences may comprise [Fc] domains. As explained in the rejection, the expression of such polypeptide sequences comprising [Fc] domains is understood to be sufficient to render the pending claim scope obvious in view of the limited guidance of record, which reasonably identifies that the limitation of the “wherein” clause is at least satisfied by at least any embodiment wherein both expressed sequences comprise an [Fc] domain (see Spec. filed 7/25/2023 at ¶[0122]). As noted above, the prior art does in fact teach such expression systems for polynucleotides encoding [Fc] domains, and therefore the structure and steps taught, suggested, and rendered obvious by the prior art are understood to fully satisfy the indefinite claim limitation. Accordingly, such arguments have been fully considered, but not deemed persuasive.
It is the Examiner’s understanding that Applicant addresses the rejection under 35 USC 103 in view of Weimer, Schellenberger, Waugh, and Bolt at page 10 (see, e.g., Reply filed 11/13/2025 at 10 at § “Bolt” to 10 at 3rd full ¶). It is the Examiner’s understanding that Applicant raises only one issue, namely that Bolt does not remedy the deficiency of Weimer (see id). This argument is not persuasive for the reasons explained in the preceding paragraph.
It is the Examiner’s understanding that Applicant addresses the Non-Statutory Double Patenting rejections at pages 10-11 (see, e.g., Reply filed 11/13/2025 at 10 at § “Double Patenting” to 11 at 1st partial ¶). It is the Examiner’s understanding that Applicant raises a single argument, namely that “this rejection be reconsidered and withdrawn on the basis that it is inconsistent with a previous (and supposedly unchanged) position regarding patentability and patentably distinct subject matter held by the Office” (see id). This argument is not persuasive as follows: First, Applicant has failed to provide any legal basis for their position and Examiner is unaware of MPEP or caselaw support for overcoming a NSDP rejection on such grounds. Applicant is invited to identify specific supporting MPEP sections or caselaw supporting the Applicant’s position. Second, the instant Application is not a divisional of any patent at issue in the NSDP rejections of record, and therefore 35 U.S.C. 121 does not apply. Third, Applicant has failed to provide any showing of consonance between the pending claims, restriction of record, and the issued claims, and therefore such arguments appear to be arguments of counsel unsupported by objective evidence or a supporting legal basis. In sum, the arguments have been fully considered, but not found persuasive. Applicant may overcome the NSDP rejections by amending the instant claims or filing a terminal disclaimer (see, e.g., MPEP § 804.02).
Accordingly, all applicable arguments have been fully considered but not found persuasive for the reasons discussed above. Accordingly, the claimed invention is not allowable.
Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
US 6,037,45228 (Minamino et al.; Mar. 14, 2000) discloses and claims FVIII covalently conjugated to vWF via a linker, namely a heterologous moiety (see, e.g., US’452 at claim 1).
US 2008/0146782 A129 (Defrees et al.; Jun. 19, 2008) discloses a “vWF-Factor VIII fusion protein having full-length Factor VIII” and also “vWF-Factor VIII fusions protein having B-domain deleted Factor VIII” (see, e.g., US’782 at ¶¶[0002], [0109], [0123], [0170], claims 1 and 4). Furthermore, US’782 teaches, discloses, and claims two fusion constructs, namely a (i) “vWF-Factor VIII fusion protein having full-length Factor VIII” and (ii) a “vWF-FVIII fusion protein having B-domain deleted Factor VIII”; and claims and discloses FVIII and vWF (see, e.g., US’782 at ¶¶[0002], [0109], [0123], [0170], claims 1 and 4). The two fusion proteins are generally referred to herein as vWF-FullFVIII and vWF-BDDFVIII or jointly as vWF-FVIII. The reference generally teaches and directs artisans to conjugate such proteins with polymers, such as PEG, to improve solubility, retention, and half-life (see, e.g., US’782 at ¶¶[0099]-[0102], claims 1 and 4).
US2011/031288130 (Dec. 22, 2011), establishes the ordinary level of skill in the XTENylation arts.
US 2016/0200794 A131 explicitly teaches and discloses covalent complexes of VWF and FVIII, wherein the complex is modified using spacer moieties and half-life extending moieties (see, e.g., US’794 at abs, claim 1, claim 17, claims 26-29). Specifically, US’794 discloses embodiments wherein VWF (or functional fragments thereof) are conjugated, via a sequence comprising a “HLEP” domain, to a sequence comprising the a2 region of FVIII, which is linked to a heterologous moiety comprising domains from FVIII (see, e.g., US’794 at abs, claim 1, claim 17, claims 26-29; see also id. at Fig. 12, reproduced below):
PNG
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223
680
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(see, also US’794 at Figs. 12(f)-12(h), 12(k), 12(n), abs, claims 1, 25, 26, 29, 36-38). US’794 expressly teaches and identifies that the HLEP portion may be an XTEN sequence (see, e.g., US’794 at ¶¶[0025], [0080], claim 29). Accordingly, the structures disclosed by US’794 include constructs that may be rewritten as
[VWF]-[XTEN]-[a2 linker comprising sequence]-[heterologous sequence].
US’794 expressly discloses that such compounds can be utilized pharmaceutically and administered to treat coagulation and bleeding disorders (see, e.g., US’794 at ¶¶[0015], [0038]-[0041], [0135], [0140]-[0141], claims 1 and 36-38). Accordingly, such applications would be obvious. US’794 discloses combinations of the different embodiments of a first and second polypeptide as shown at Figure 12 to form additional unspecified FVIII/VWF complexes (see, e.g., US’794 at ¶[0110]). Furthermore, US’794 discloses that bleeding and coagulation disorders are routinely treated with FVIII (see, e.g., US’794 at ¶¶[0004]-[0008], discussing typical treatments and known FVIII variants). Accordingly, US’794 fairly discloses that FVIII and the inventive FVIII/vWF complexes are both compositions disclosed as suitable and useful for the same purpose, namely the treatment of bleeding and coagulation disorders (id.).
WO 2011/060242 A232 describes modified VWF polypeptides conjugated to IgG Gc domains (see, e.g., WO’242 at abs, 3 at § Brief Description) and a chimeric protein comprising a first amino acid sequence comprising VWF and a heterologous sequence, wherein the resulting protein is capable of binding FVIII (see, e.g., WO’242 at 7 at § Detailed Description, 7-8 at bridging ¶), and wherein a linker may be present between the VWF and heterologous sequence (see, e.g., id. at 11-12 at bridging ¶), and wherein the polypeptide may be further conjugated to a compound that increases the half-life of the polypeptide (see, e.g., id. at 13 at 2nd ¶). Furthermore, WO’242 also describes and identifies protein complexes comprising the described VWF-Linker-heterologous fusion constructs along with FVIII (see, e.g., id. at 26 at § IV), wherein the VWF-Linker-Heterologous:FVIII complexes can be present as a dimer via Fc polypeptides and “joined by disulfide bonds” (see, e.g, id. at 27 at 4th full ¶), and are understood to be suitable for extending FVIII plasma half-life (see, e.g., id. at 34 at § VI, claims 1, 5, 8, 15).
WO 2010/111414 A133 describes modified FVIII derivatives and identifies the relationship between FVIII and VWF (see, e.g., WO’414 at abs, ¶¶[007]-[008], [157]-[158]).
WO 2009/156137 A134 discloses the typical use of vWF and FVIII in the art, which included use in pharmaceutical compositions suitable for the treatment of coagulation disorders, including Hemophilia A and von Willebrand’s Disease (see, e.g., WO’137 at 6 at lines 10-15). Therefore the use of a “second protein” comprising FVIII is routine in the art and commonly utilized with vWF proteins (see id.). Furthermore, formulating such compounds in pharmaceutical compositions would be obvious to one of ordinary skill in the art, because such formulations would be required to utilize such therapeutics for their art-recognized purpose, namely treating Hemophilia A and VWD.
WO2013/08385835 teaches compositions comprising two polypeptides, namely a first polypeptide comprising a VWF fragment and a second polypeptide comprising FVIII (see, e.g., WO’858 at 12). Regarding the VWF protein fragment and Cys1099 and Cys1142 mutations, WO’858 identifies that the VWF fragment may comprise the D’ and D3 domains, wherein Cysteine 1099 and cysteine 1142 are substituted with another amino acid (see, e.g., WO’858 at claims 10-12, page 15, SEQ ID NO: 10-11, noting that 1099 and 1142 may be serine or another amino acid). WO’858 identifies that the substitution of Cys1099 and Cys1142 in the D3 domain of VWF provides a predicted and expected result, namely the prevention of VWF dimerization, which is expected to “lead to a simpler product purification procedure” (see, e.g., WO’858 at 12 at lines 5-17).
Newell et al.36 teaches and identifies that residues “Glu720, Asp 721, Glu724, and Asp725 likely constitute an exosite-interactive region in factor VIII facilitating cleavage[]” (see, e.g., Newell at abs, 8786-8787 at bridging ¶, 8792 at col II at § Discussion at 1st and 2nd full ¶¶, Table 2 on 8791, Table 3 on 8793). Accordingly, an artisan reading US’907 in view of Newell would reasonably appreciate and recognize that the “highly preferred” linker encompassing the Arg740 thrombin cleavage site (see, e.g., US’904 at ¶¶[0145], [0147]) should necessarily encompass at least residues Glu720 to Arg740 of SEQ ID NO: 15 of US’904.
Newell et al.37 teaches that the P3-P3’ residues surrounding the Arg740 cleavage site are EPR*SFS (where “*” denotes the cleavage site) (see, e.g., Abstract at 1 of the pdf) and are optimal, but not required for cleavage (see, e.g., Abstract at 1-2).
Schellenberger et al.38 establishes that XTEN sequences are prior art elements (see, e.g., Schellenberger at abs, supp. page 18/19 to 19/19) used to extend the half-life of therapeutic polypeptides (see, e.g., id. at abs). The teachings of Schellenberger have been extensively discussed in a preceding rejection and that discussion is incorporated herein. In brief, XTENylation of therapeutics provides numerous expected advantages including extending half-life (see, e.g., Schellenberger, 1189 at col I at last ¶ to 1189 at col II at penultimate ¶), decreased dosing frequencies (id. at abs), and XTEN has multiple advantages relative to traditional PEGylation (see, e.g., id. at 1186 col I 1st ¶ to col II at 1st partial ¶, 1189 at col I at last ¶, 1190 at col I at 1st full ¶). Notably, XTEN had been successfully reduced to practice with other coagulation factors (see, e.g., id. at Supp. 13/19 to 14/19, and 18/19 to 19/19). Accordingly, an artisan would desirably utilize XTEN with therapeutic proteins for the same purpose of predictably and expectedly extending the half-life of therapeutic proteins (see, e.g., id. at 1186 col I 1st ¶ to col II at 1st full ¶, noting that references 12-13 disclose prior art unstructured peptides). Regarding specific XTEN sequences recited in the instant claims, Schellenberger discloses and exemplifies the use of XTEN having a length of 864 residues, 576 residues, and 288 residues (see, e.g., Schellenberger at Table 1 on 1188, supp. at 18/19 to 19/19) and discloses each sequence (compare Schellenberger at supp. at 18/19 to 19/19 with instant SEQ ID NO: 47, showing that both documents disclose AE864). Critically, AE864 comprises all “AE motifs” including instant SEQ ID NOs: 53, 54, 55, and 56 (compare instant SEQ ID NO: 47 with instant Table 2A, identifying the 12-mer motifs used to make longer XTEN sequences).
US1203092539 claims related subject matter, which differs from the instant claim scope because it lacks an X-V-P-R cleavage site as required by the instant claims (compare US’925 at claims with instant claim 98).
Conclusion
No claims are allowed.
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 RANDALL L BEANE whose telephone number is (571)270-3457. The examiner can normally be reached Mon.-Fri., 7 AM to 2 PM ET.
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, Lianko G. Garyu can be reached at (571) 270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/RANDALL L BEANE/Primary Examiner, Art Unit 1654
1 Cited in IDS filed 12/22/2023 as cite No. 184.
2 Positions 1-1242 correspond to a VWF protein comprising a signal peptide, a D1D2 domain, a D’ domain, and a D3 domain. The D’ domain is shown with a double underline. The D3 domain is shown with a dotted underline.
3 Positions 1243-1530 correspond to a first XTEN sequence corresponding to instant SEQ ID NO: 43 (i.e., XTEN AE288), which is shown with a grey highlight.
4 Positions 1531-1551 correspond to a VWF linker comprising a X-V-P-R sequence, wherein X is Leucine; this is indicated in bold.
5 Positions 1552 to 1778 correspond to a first immunoglobulin constant region.
6 This is understood to be a B domain deleted FVIII protein with R1648A substitution fused to an Fc region, wherein an XTEN AE288 is inserted at amino acid 745 corresponding to mature full length FVIII.
7 Amino acids 1-764 and 1068-1751 were identified as corresponding to a FVIII protein.
8 Amino acids 765-767 are not identified as corresponding to FVIII or XTEN (see, e.g., Remarks filed 6/6/2025 at 6-8), and are indicated by underline.
9 Amino acids 768-1055 correspond to the XTEN sequence of SEQ ID NO: 43 (i.e., AE288) and are shown with grey highlight (see, e.g., Remarks filed 6/6/2025 at 6-8).
10 Amino acids 1056-1067 are not identified as corresponding to FVIII or XTEN (see, e.g., Remarks filed 6/6/2025 at 6-8), and are indicated by dotted underline.
11 Amino acids 1752 to 1978 comprise an immunoglobulin constant region (see, e.g., Remarks filed 6/6/2025 at 6-8), which is shown in bold.
12 Cited in previous action
13 Cited in previous action
14 Cited in previous action
15 Waugh et al. An overview of enzymatic reagents for the removal of affinity tags. Protein Expr Purif. 2011 Dec;80(2):283-93. doi: 10.1016/j.pep.2011.08.005. Epub 2011 Aug 19. PMID: 21871965; PMCID: PMC3195948; cited in previous action.
16 “HLEP” is used by US’907 to refer generically to a “Half-life Enhancing Polypeptide” (see, e.g., US’907 at ¶¶[0149]-[0150]).
17 Cited in previous action
18 Cited in previous action
19 Waugh et al. An overview of enzymatic reagents for the removal of affinity tags. Protein Expr Purif. 2011 Dec;80(2):283-93. doi: 10.1016/j.pep.2011.08.005. Epub 2011 Aug 19. PMID: 21871965; PMCID: PMC3195948; cited in previous action.
20 Cited in previous action
21 Cited in previous action
22 Referred to as a “thrombin cleavable linker” in US’291.
23 Cited in previous action
24 See, e.g., MPEP § 804(II)(B), noting that “In determining whether a nonstatutory basis exists for a double patenting rejection, the first question to be asked is: Is any invention claimed in the application anticipated by, or an obvious variation of, an invention claimed in the patent? If the answer is yes, then a nonstatutory double patenting rejection may be appropriate.”
25 Cited in previous action
26 Cited in previous action
27 Referred to as a “thrombin cleavable linker” in US’291.
28 Cited in previous action
29 Cited in previous action
30 Cited in previous action
31 Cited in previous action
32 Cited in IDS filed 12/22/2023 as cite No. 184.
33 Cited in IDS filed 12/22/2023 as cite No. 174; Zhao et al.; Sept. 30, 2010.
34 Cited in IDS filed 12/22/2023 as cite No. 167.
35 Cited in IDS filed 12/22/2023 as cite No. 199.
36 Newell et al., Acidic Residues C-terminal to the A2 domain Facilitate Thrombin-Catalyzed Activation of Factor VIII, Biochemistry, vol. 47:8786-8795 (2008); hereafter “Newell”; cited in IDS filed 12/22/2023 as cite No. 578.
37 Newell et al.,Residues Surrounding Arg372, Arg740, and Arg1689 Contribute to the Rates of Thrombin-Catalyzed Cleavage of Factor VIII (Meeting Abstract), Blood, Vol. 114(22):349 (Nov. 20, 2009); hereafter “Abstract”; cited in IDS filed 12/22/2023 as cite No. 579.
38 Schellenberger et al., A recombinant polypeptide extends the in vivo half-life of peptides and proteins in a tunable manner, Nature Biotechnology, vol. 27(2):1186-1190 with 21 pages of Supplemental Online Material (Nov. 15, 2009); hereafter “Schellenberger”; cited in IDS filed 12/23/2023 as cite No. 764.
39 Cited in previous action