Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 5/26/2026 has been entered.
1. Claims 1-84, 86, 88-90 and 92-95 have been cancelled. Claims 105-106 are new. Claims 85, 91 and 101-103 have been amended. Claims 85, 87, 91 and 96-106 are pending and are under examination.
Claim Rejections Withdrawn
The rejection of claims 88 and 89 under 35 U.S.C. 101 because the claimed invention is directed to a composition of matter without significantly more is withdrawn in view of the cancellation of the claims.
The rejection of claim(s) 85, 86 and 88 under 35 U.S.C. 102(a)(1) as being anticipated by Matsuda et al. US 6,372,225 4/16/2002 cited in IDS is withdrawn in view of the amendment to the claims.
The rejection of claim(s) 85 and 89 under 35 U.S.C. 103 as being unpatentable over Matsuda et al. US 6,372,225 4/16/22 cited in IDS in view of as evidenced by Wolfe et al. US 8,703,733 B2 2/22/2014 is withdrawn in view of the amendment to the claims.
The rejection of claim(s) 91, 93-94, 96-97 and 101-104 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Shin et al. WO 2021/021729 2/4/2021 as evidenced by Wolfe et al. US 8,703,733 B2 2/22/2014 is withdrawn in view of the amendment to the claims.
The rejection of claim(s) 91, 93-94, 96, 97 and 101-104 under 35 U.S.C. 103 as being unpatentable over Shin et al. WO 2021/021729 2/4/2021 in view of Wolfe et al. US 8,703,733 B2 2/22/2014 is withdrawn in view of the amendment to the claims.
The rejection of claim(s) 91, 93, 96, 97 and 101-104 under 35 U.S.C. 103 as being unpatentable over Shin et al. WO 2021/021729 2/4/2021 in view of Matsuda et al. US 6,372,225 4/16/2002 is withdrawn in view of the amendment to the claims.
Claim Rejections Maintained
Claim Rejections - 35 USC § 101
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
2. The rejection of claims 85 and 87 under 35 U.S.C. 101 because the claimed invention is directed to a product of nature without significantly more is maintained.
The claim(s) recite(s) an isolated tetanus toxin protein variant, consisting of the segment C of the tetanus toxin protein and the partial segment of the translocation region of the tetanus toxin protein, wherein the variant is N-terminally truncated compared to the wild-type tetanus toxin protein and consists of the amino acid sequence set forth in SEQ ID NO: 1 or SEQ ID NO: 2.
The full length sequence of tetanus toxin protein is 1315 amino acids long. SEQ ID NO: 1 and SEQ ID NO: 2 represent fragments of the full length sequence of tetanus toxin protein. It is noted that claim 87 recites that the partial segment of the translocation region “comprises” amino acids 829-864. Due to the word “comprises” which is open-ended, the partial segment of the translocation region can be larger than that of claim 85.
The claim is analyzed according to the subject matter eligibility test set forth in MPEP 2106 (III).
Step 1: Claim 85 and 87 are drawn to composition of matter.
Step 2A: The isolated toxin variant is drawn to a product of nature.
The claimed toxin fragments have different structural characteristics than naturally occurring tetanus toxin protein because they have shorter amino acid sequence as compared to the natural full length tetanus toxin protein. Due to this fact, the tetanus toxin protein variants are nature-based derived from full length tetanus toxin protein sequence they are compared to their natural counterpart.
Tetanus toxin (TT) has different biological properties associated with distinct parts of the TT structure namely fragment A, fragment B and fragment C. Fragment A comprises the catalytic domain having the toxic endopeptidase activity, fragment B is non-toxic and is the translocation domain and fragment C is the domain capable of binding to a receptor.
The fragments of tetanus toxin being claimed encompass the non-toxic portions of tetanus toxin i.e. fragment C (segment C) and parts of fragment B. See figure 1 below. The closest natural counterpart to the fragments being claimed is the protein sequence covering fragment B and fragment C based on the structure of tetanus toxin which covers residue 458 to 1315 of tetanus toxin protein sequence. See figure 1 of Bayart et al. Pharmaceuticals. 2022; 15(6):756.
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The claimed fragments are different from the fragment B and fragment C sequence (residues 458 to 1315) because they are fragments but are not markedly different because the protein sequence of these fragments as found in residues 458 to 1315 remains the same.
The claimed variants do not exhibit a markedly different functional profile in comparison to the non-toxic portions of tetanus toxin (fragment B and C) because the fragments will continue to be non-toxic as these parts of the toxin do not have the toxic endopeptidase activity found in fragment A.
The addition of a partial amino acid sequence of fragment B with fragment C is not enough to make the claimed fragments markedly different because the sequence of the fragments is found in non-toxic portion of tetanus toxin covering residues 458-1315.
The location and order of the amino acid sequence of the TT fragment being claimed existed in nature in the fragment B and fragment C sequence (residues 458-1315). See figure 1 above.
Even if Applicants have discovered the folding properties of these fragments, this is not enough. The courts have emphasized that to show a marked difference, a characteristic must be changed as compared to nature, and cannot be an inherent or innate characteristic of the naturally occurring counterpart or an incidental change in a characteristic of the naturally occurring counterpart. Myriad, 569 U.S. at 580, 106 USPQ2d at 1974-75.
Accordingly the claim is directed to an exception and because the claim does not include additional features that could add significantly more to the exception, the claim does not qualify as eligible subject matter.
3. Response to Applicants Argument
Applicants argue that the claimed protein is man-made, structurally engineered and functionally distinct and does not exist in nature.
Applicant stated that the proteins set forth in SEQ ID NO: 1 and 2 are man-made, deliberately constructed protein variants that differ from the naturally occurring tetanus toxin proteins and that these specific variants do not occur naturally and are not naturally generated through typical biological process and the variants are generated by removing amino acids at the N-terminus and the C-terminus.
Applicants argument have been carefully considered but is not found persuasive.
The Supreme Court in Myriad (Association for Molecular Pathology ET AL., v. Myriad Genetics, INC. ET AL. 133 S. Ct. 2107 (2013)) made clear, neither naturally occurring compositions of matter, nor synthetically created compositions that are structurally identical to the naturally occurring compositions, are patent eligible. Id. at 2117.
The Supreme Court in Myriad held ineligible claims directed to segments as short as 15 nucleotides, the same length as the primer claims at issue here, suggesting that even short strands identical to those found in nature are not patent eligible. See University of Utah Research Foundation, the Trustees of the University of Pennsylvania, HSC Research and Development Limited Partnership, Endorecherche, Inc., and Myriad Genetics, Inc. v. Ambry Genetics Corporation 774 F.3d 755 (2014) (herein after Ambry Genetics)
Similarly, in the instant case the fragments of tetanus toxin protein whose sequence is found in fragment B and fragment C portion of tetanus toxin is ineligible.
Applicants argue that natural tetanus toxin protein is a potent neurotoxin and in contrast, the claimed variants exhibit a markedly different functional profile and maintains corrected folded structure, stability and binding function while lacking toxicity and this is significantly different from the naturally occurring tetanus toxin protein.
Applicants argument has been considered but is not found persuasive. Tetanus toxin (TT) has different biological properties associated with distinct parts of the TT structure namely fragment A, fragment B and fragment C. Fragment A comprises the catalytic domain having the toxic endopeptidase activity, fragment B is non-toxic and is the translocation domain and fragment C is the domain capable of binding to a receptor. See specification.
The fragments of tetanus toxin being claimed encompass the non-toxic fragment C (segment C) and parts of the non-toxic fragment B.
Due to the structure of tetanus toxin the closest natural counterpart to the fragments being claimed is the protein sequence covering fragment B and fragment C based on the structure of tetanus toxin (TT) which covers residue 458 to 1315 of tetanus toxin protein sequence. The closest natural counterpart is not the full length protein sequence because of the different biological properties associated with distinct parts of the TT structure namely fragment A, fragment B and fragment C. See figure 1 of Bayart et al. Pharmaceuticals. 2022; 15(6):756.
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Fragment A comprises the catalytic domain having the toxic endopeptidase activity, fragment B is non-toxic and is the translocation domain and fragment C is the domain capable of binding to a receptor.
The fragments of tetanus toxin being claimed encompass the non-toxic portions of tetanus toxin i.e. fragment C (segment C) and parts of fragment B (segment C). See figure 1 below. The closest natural counterpart to the fragments being claimed is the protein sequence covering fragment B and fragment C based on the structure of tetanus toxin structure which covers residue 458 to 1315 of tetanus toxin protein sequence.
The claimed fragments are different from the fragment B and fragment C sequence (residues 458 to 1315) because they are fragments but are not markedly different because the protein sequence of these fragments as found in residues 458 to 1315 remains the same.
The claimed variants do not exhibit a markedly different functional profile in comparison to the non-toxic portions of tetanus toxin (fragment B and C) because the fragments will continue to be non-toxic as these parts of the toxin do not have the toxic endopeptidase activity found in fragment A.
The addition of a partial amino acid sequence of fragment B with fragment C is not enough to make the claimed fragments markedly different because the sequence of the fragments as found in the non-toxic portion of tetanus toxin covering residues 458-1315 did not change.
The location and order of the amino acid sequence of the TT fragment being claimed existed in nature in the fragment B and fragment C sequence (residues 458-1315). See figure 1 above.
Even if Applicants have discovered the folding properties of these fragments, this is not enough. The courts have emphasized that to show a marked difference, a characteristic must be changed as compared to nature, and cannot be an inherent or innate characteristic of the naturally occurring counterpart or an incidental change in a characteristic of the naturally occurring counterpart. Myriad, 569 U.S. at 580, 106 USPQ2d at 1974-75.
See Ambry Genetics disclosing “the Court held ineligible the isolated DNA claims, explaining: "Myriad did not create or alter any of the genetic information encoded in the BRCA1 and BRCA2 genes. The location and order of the nucleotides existed in nature before Myriad found them." Myriad, 133 S.Ct. at 2116. Rather, "Myriad's principal contribution was uncovering the precise location and genetic sequence of the BRCA [genes]." Id. Even if Myriad made a "[g]roundbreaking, innovative, or even brilliant discovery," id. at 2117, that is not enough.”
Furthermore, it makes no difference that the protein fragments are synthetically replicated. See Ambry Genetics disclosing “as the Supreme Court made clear, neither naturally occurring compositions of matter, nor synthetically created compositions that are structurally identical to the naturally occurring compositions, are patent eligible. Id. at 2117. After all, as the district court in the earlier Myriad case and our opinion in Myriad made clear, isolated DNA is routinely synthetically created. See Ass'n for Molecular Pathology v. U.S. Patent and Trademark Office, 702 F.Supp.2d 181, 217 (S.D.N.Y.2010) (construing "isolated DNA" to "include both DNA originating from the cell as well as DNA synthesized through chemical or heterologous biological means"); Myriad, 689 F.3d at 1313 (explaining that "[i]solated DNA has been cleaved ... or synthesized to consist of just a fraction of a naturally occurring DNA molecule" and that "isolated DNA results from human intervention to cleave or synthesize a discrete portion of a native chromosomal DNA").”
The fragments of a naturally occurring fragment B and fragment C sequence covering residues 458-1315 is not patent eligible as set forth above. The situation is similar with regards to DNA fragments of a longer DNA sequence as disclosed in Ambry Genetics wherein it is disclosed that “the Supreme Court held ineligible claims directed to segments as short as 15 nucleotides, the same length as the primer claims at issue here, suggesting that even short strands identical to those found in nature are not patent eligible.”
For these reasons, the rejection is maintained.
4. The rejection of claim(s) 87 and 98-100 under 35 U.S.C. 102(a)(1) as being anticipated by Matsuda et al. US 6,372,225 4/16/2002 cited in IDS is maintained.
5. Response to Applicant’s Argument
Applicant argues that claim 85 is amended to recite that the isolated tetanus toxin protein variant consist of the segment C of the tetanus toxin protein and the partial segment of the translocation region of the tetanus toxin protein, and is set forth in SEQ ID NO: 1 or SEQ ID NO: 2.
Regarding claim 87: Applicants argument has been carefully considered but is not found persuasive. This is because claim 87 states that the partial segment of the translocation region comprises amino acids 829-864. “Comprises” as used in claim 87 is open-ended and the partial segment of the translocation region can be larger than that found in claim 85.
Regarding claims 98-100: Applicants argument has been considered but is not found persuasive. SEQ ID NO: 1 and SEQ ID NO: 2 represent fragment sequences of the full length tetanus toxin protein.
A nucleic acid molecule, comprising a sequence encoding the tetanus toxin protein variant reads on a nucleic acid molecule comprising a larger sequence that encodes the tetanus toxin amino acid sequence fragments.
The tetanus toxin protein fragments disclosed by Matsuda are larger i.e. SEQ ID NO: 16 or SEQ ID NO: 17 comprises SEQ ID NO: 1 and SEQ ID NO: 16 and SEQ ID NO: 17 of Matsuda comprises SEQ ID NO: 2. See sequence alignment in the previous Office Action.
However, a nucleic acid molecule comprising a sequence encoding the tetanus toxin protein fragments of claim 85 can encompass a larger nucleic acid sequence because claim 98 is “open-ended” due to the word “comprising”.
Therefore, Matsuda still reads on claims 98-100 because a nucleic acid molecule (DNA), comprising a sequence encoding the tetanus toxin protein variant (a tetanus toxin functional fragment antigen -FFA represented by SEQ ID NO: 16 and SEQ ID NO: 17); a vector comprising the DNA; and a host cell comprising the nucleic acid molecule. See column 6 lines 38-46.
New Claim Rejections
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
6. Claim 97 is 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.
Claim 97 is drawn to a method for improving immunogenicity comprising the step of: providing a polysaccharide protein conjugate according to claim 91. Claim 97 is vague and indefinite because it is not clear how simply providing a polysaccharide protein conjugate according to claim 91 results in improvement of immunogenicity.
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.
7. Claim 87 is 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.
Claim 87 is drawn to the isolated tetanus toxin protein variant according to claim 85, wherein the partial segment of the translocation region comprises amino acids 829-864. Due to the recitation that the partial segment of the translocation region “comprises”, the partial segment of the translocation region can be larger than the partial segment of the translocation region of the variant of claim 85 which consists of SEQ ID NO: 1 or SEQ ID NO: 2. Thus, claim 87 fails to further limit the subject matter of the claim upon which it depends.
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.
8. Claims 98, 99 and 100 are rejected under 35 U.S.C. 101 because the claimed invention is directed to natural phenomenon without significantly more.
The claim(s) recite(s) a nucleic acid molecule comprising a sequence encoding the isolated tetanus toxin protein variant consisting of the segment C of the tetanus toxin protein and the partial segment of the translocation region of the tetanus toxin protein, wherein the variant is N-terminally truncated compared to the wild-type tetanus toxin protein and consists of the amino acid sequence set forth in SEQ ID NO: 1 or SEQ ID NO: 2.
SEQ ID NO: 1 is a fragment of the full length tetanus toxin protein sequence covering residues 829-1315 of the full length tetanus toxin protein sequence which is 1315 amino acids long.
SEQ ID NO: 2 is a fragment of the full length tetanus toxin protein sequence covering residues 829-1315 of the full length tetanus toxin protein sequence which is 1315 amino acids long.
A nucleic acid molecule comprising a sequence encoding SEQ ID NO: 1 or SEQ ID NO: 2 reads on the gene encoding tetanus toxin protein. The gene encoding tetanus toxin is a nucleic acid molecule comprising a sequence encoding SEQ ID NO: 1 or SEQ ID NO: 2. That is, the gene encoding tetanus toxin comprises the sequence encoding the isolated protein fragments of claim 85.
The claimed nucleic acid has a different structural characteristics than naturally occurring tetanus toxin gene, because the chemical bonds at each end were severed in order to isolate it from the plasmid on which it occurs in nature, but has the same nucleotide sequence as the natural gene. The claimed nucleic acid has no different characteristics i.e. it encodes the same protein as the natural gene. The claimed nucleic acid which reads on the tetanus toxin gene as explained above is otherwise unchanged nucleic acid and is not eligible because it is not different enough from what exists in nature to avoid improperly tying up the future use and study of the natural tetanus toxin gene. The claimed nucleic acid is different, but is not markedly different from its natural counterpart in its natural state and thus is a “product of nature” exception. Accordingly the claim is directed to an exception and because the claim does not include additional features that could add significantly more to the exception, the claim does not qualify as eligible subject matter.
Claim 99 is drawn to a vector comprising the nucleic acid molecule of claim 98. The specification teaches that the term “vector” generally refers to a vector that contains the regulatory sequences necessary for the transcription and translation of one or more cloned nucleic acid, and thus allows the transcription and cloning of the nucleic acid molecule. The natural plasmid is a vector that contains the regulatory sequences necessary for the transcription and translation of the tetanus toxin gene, and thus allows the transcription of the nucleic acid molecule encoding tetanus toxin. This is the natural counter part to the vector of claim 99.
The claimed vector has no different characteristics from the natural counterpart because it contains the regulatory sequences necessary for the transcription and translation of one or more cloned nucleic acid as it encodes the same protein as in the natural counterpart plasmid. Cloning nucleic acids is routinely practiced and as claimed there is no difference in the nucleic acid in the vector and the nucleic acid in the natural plasmid (vector) encoding a nucleic acid molecule comprising a sequence encoding the tetanus toxin protein variant of claim 85.
The claimed vector which reads on the natural plasmid encoding the tetanus toxin gene is otherwise unchanged nucleic acid and is not eligible because it is not different enough from what exists in nature to avoid improperly tying up the future use and study of the natural plasmids encoding tetanus toxin gene. The claimed vector is different, but is not markedly different from its natural counterpart in its natural state and thus is a “product of nature” exception. Accordingly the claim is directed to an exception and because the claim does not include additional features that could add significantly more to the exception, the claim does not qualify as eligible subject matter.
Claim 100 is drawn to a cell comprising the nucleic acid molecule of claim 98. The claimed nucleic acid of claim 98 has no different characteristics i.e. it encodes the same protein as the natural gene as set forth above. A cell comprising said nucleic acid molecule has no different characteristic from the natural counterpart which is the Clostridium tetani bacterial cell that comprises a nucleic acid molecule that encodes the natural tetanus toxin gene.
The claimed cell is not different enough from what exists in nature to avoid improperly tying up the future use and study of the natural counterpart which is the Clostridium tetani cell comprising the nucleic acid molecule encoding the tetanus toxin gene. The claimed cell is not markedly different from its natural counterpart in its natural state and thus is a “product of nature” exception.
Accordingly the claim is directed to an exception and because the claim does not include additional features that could add significantly more to the exception, the claim does not qualify as eligible subject matter.
Status of Claims
9. Claims 85, 87 and 97-100 are rejected.
10. Claims 91, 96 and 101-106 are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to OLUWATOSIN A OGUNBIYI whose telephone number is (571)272-9939. The examiner can normally be reached IFP.
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/OLUWATOSIN A OGUNBIYI/ Primary Examiner, Art Unit 1645
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