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 .
DETAILED ACTION
1. Applicant’s amendments/responses filed 5/6/25, 11/14/25 and 1/14/22 are acknowledged and have been entered.
2. Applicant's election with traverse of the following species in Applicant’s response filed 11/14/25 is acknowledged:
a specific species of fully defined chimeric HA protein:
-an amino acid sequence of SEQ ID NO: 4 (recited in claim 32) as the specific first and second HA1 subunits;
-H7 subtype influenza virus (recited in claim 22) as the specific HA2 subunit;
-the limitations recited at parts 1, 2 and 3 of claim 28 as the one or more specific portions and/or interfaces; and
a specific species of influenza virus that is H7N9 that is recited in claim 37.
The basis for Applicant’s traversal is of record in the said response on page 2.
However, each species must be searched separately using different search queries and each different SEQ ID NO must be searched separately against protein databases. As stated in the restriction requirement mailed 9/17/25, the chimeric HA proteins and their recited variants have different primary amino acid sequences, derive from different influenza viral subtypes, and induce immune responses against different influenza virus subtypes.
The requirement is still deemed proper and is therefore made FINAL.
Accordingly, claim 21 (non-elected species) is withdrawn from further consideration by the Examiner, 37 CFR 1.142(b), as being drawn to anon-elected invention.
Claims 21-30 and 32-39 read upon the elected species. Upon consideration of the prior art, search and examination are being extended to SEQ ID NO: 3 and 5-8 and the species enunciated in the art rejections below in this office action.
Claims 21-30 and 32-39 are being examined as they read upon SEQ ID NO: 3-8 as well as the species enunciated in the art rejections below in this office action.
Claims 21 and 36 are independent claims.
3. The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
4. The disclosure is objected to because of the following informalities:
The specification at the brief description of the drawings refers to “color”, “colored”, or “colors” in the figures; however, it appears that only black and white drawings were submitted.
Appropriate correction is required.
5. 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.
6. Claims 21-30 and 33-38 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. This is a written description rejection.
Applicant has broadly claimed:
a) a chimeric HA protein comprising an HA1 subunit and an HA2 subunit, wherein the HA 1 subunit is composed of a first domain derived from a parental HA1 subunit of a first subtype influenza virus and a second domain derived from a parental HA1 subunit of a second subtype influenza virus (as is recited in instant base claim 21), and including wherein
the first and second subtypes of influenza virus are independently select from the group consisting of those recited, provided the first and second subtypes are different (dependent claim 22);
the HA1 subunit has an amino acid identity less than 100% as compared with the parental HA1 subunit of the first subtype influenza virus (claim 23);
the HA1 subunit has an amino acid identity of at least 30% as compared with the parental HA1 subunit of the first subtype influenza virus (claim 24);
the HA1 subunit has an amino acid identity of between 70% and 95% as compared with the parental HA1 subunit of the first subtype as compared with the parental HA1 subunit of the first subtype influenza virus (claim 25);
the amino acid identity of the HA1 subunit compared to the parental HA1 subunit of the first subtype influenza virus is between 88% and 91% (claim 26);
the chimeric protein comprises at least one of the limitations recited in dependent claim 28 (amino acid residues in particular locations of the chimeric HA protein);
the first subtype influenza virus is an H7 subtype influenza virus (dependent claim 29);
the second subtype influenza virus is an H3 subtype influenza virus (dependent claim 30);
the HA2 subunit is an HA2 subunit of the first subtype influenza virus (dependent claim 33);
a vaccine composition comprising the HA protein of claim 21, wherein the chimeric HA protein is present in an amount effective in preventing influenza virus infection (claim 34), and further comprising an adjuvant (claim 35);
b) a method of including an immune response against an influenza virus in a subject in need thereof, comprising administering the vaccine composition according to claim 34 to the subject (as is recited in instant base claim 36), including wherein the influenza virus is H7N9 (Applicant’s elected species recited in dependent claim 37) or including wherein the HA1 subunit of the chimeric HA protein has an amino acid identity of at least 30% and less than 100% as compared with an HA1 subunit of the influenza virus (as is recited in dependent claim 38).
The specification does not disclose a representative number of species of such chimeric HA protein or method of inducing an immune response against an influenza virus in a subject in need thereof by administering a vaccine composition according to claim 34 comprising the said chimeric protein, nor sufficient relevant identifying characteristics in the form of structure or functional characteristics coupled with a known or disclosed correlation between structure and function.
This is so because the specification discloses that the definition of “domain” encompasses non-continuous (non-contiguous) amino acid residues and/or peptides and those non-continuous residues and/or peptides that form a “domain” must possess the functional property of assembling as an integrated and structurally interacting domain”. The specification and the art evidence that the amino acid sequence of the chimeric proteins cannot be envisioned a priori (experimentation must be engaged in to determine their amino acid sequences). In addition, the specification discloses that the HA protein of an influenza virus is comprised of HA1 and HA2 subunits, of which the HA1 subunit contains a receptor binding site with the functional property of binding to sialic acid receptors, whereas the HA2 subunit contains a fusion peptide and TM domain that are responsible for the functional property of trimerization. The specification only discloses two chimeric proteins that have HA1 domains from two species of Group II influenza viruses, H7 and H3, that possess the functional property of domains that assemble as integrated and structurally interaction domains, that comprise a domain having the functional property of sialic acid binding and a domain having the functional property of trimerization (whereas four other species disclosed in the specification having HA1 domains from the same H7 and H3 proteins in different combinations do not possess the requisite functional properties). Neither the recitation of first and second HA domains from two different influenza subtype viruses, nor the recitation of the particular two subtypes, nor the percent amino acid identity with the parental HA1 subunit(s), nor the recitation of amino acid residues in HA1 or HA2 or at the interface of the HA1-HA2 recited in claim 28 provides adequate written description since these said limitations do not provide a structure/function relationship.
An applicant shows possession of the claimed invention by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention. Lockwood v. Amer. Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997). Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was "ready for patenting" such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaff v. Wells Elecs., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641, 1647 (1998); Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406; Amgen, Inc. v. Chugai Pharm., 927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991) (one must define a compound by "whatever characteristics sufficiently distinguish it"). "Compliance with the written description requirement is essentially a fact-based inquiry that will ‘necessarily vary depending on the nature of the invention claimed.' " Enzo Biochem, 323 F.3d at 963, 63 USPQ2d at 1612. An invention described solely in terms of a method of making and/or its function may lack written descriptive support where there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function. See MPEP 2163 I.A.
An applicant may also show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613 (quoting the Written Description Guidelines, 66 Fed. Reg. at 1106, n. 49, stating that "if the art has established a strong correlation between structure and function, one skilled in the art would be able to predict with a reasonable degree of confidence the structure of the claimed invention from a recitation of its function".). "Thus, the written description requirement may be satisfied through disclosure of function and minimal structure when there is a well-established correlation between structure and function." See MPEP 2163 II.3.
The specification discloses that “the term “chimeric HA protein,” “chimeric protein, “ or “chimeric subunit” as used herein refers to a single polypeptide unit that comprises at least two heterological domains joined by a peptide bond(s), wherein the different domains are not naturally occurring within the same polypeptide unit. As to the amino acid sequence of the chimeric protein, each heterological domain may correspond to non-continuous amino acids or a number of peptide fragments. These non-continuous amino acids and peptide fragments may assemble as an integrated and structurally interacting domain”(paragraph spanning pages 11-12).
The specification further discloses “The term “domain” or “protein block” as used herein refers to a set of at least one amino acid, at least one peptide, or a combination thereof in a protein. That is to say, a domain of a protein may include only one amino acid, a plurality of non-continuous amino acids, only one peptide, a plurality of peptide[s], or a combination thereof” (page 12 at lines 11-14).
The specification discloses that the “HA protein of an influenza virus” is comprised of HA1 and HA2 subunits, of which the HA1 subunit contains a receptor binding site (RBS) for binding to sialic acid receptors, whereas the HA2 subunit contains a fusion peptide and TM domain that are responsible for trimerization (paragraph spanning pages 1-2).
The specification discloses “In one embodiment of the present disclosure, the second domain in the chimeric HA1 subunit is at least one portion of an HA structural region selected from the group consisting of a fusion peptide pocket, and HA1 region near the spring-loaded coiled-coil helix of the HA2 subunit, and HA1-HA1 interface, and an HA1-HA2 interface (page 14 at lines 10-13).
The specification discloses that in some embodiments of the present disclosure, the first and second subtype influenza viruses may be independently selected from Group I influenza viruses such as H1, H2, H5, H6, H8, H9, H11-H13 and H16-H18 or Group II influenza viruses such as H3, H4, H7, H10, H14, and H15 subtype influenza viruses (page 11 at lines 11-18).
The specification does not disclose a limiting definition for “derived from”.
Evidentiary reference Sautto et al. (Virol. Journal, 2018, 15(17): 1-12, IDS reference) teaches that within a subtype, there is up to about 15% amino acid sequence diversity, whereas HA proteins between subtypes have 40% or 60% sequence diversity, which highlight the great hypervariable nature of these viral proteins (page 2 at column 2 at the first full paragraph). Sautto e. al. further teach that influenza A viruses circulate in many avian species and infect several mammalian species including humans, wherein influenza B viruses infect only humans, influenza C viruses infect humans and pigs, and influenza D viruses primarily infect cattle (first paragraph of Introduction section on page 2). Sautto et al. teach that each influenza virus is further classified on the basis of the surface glycoproteins HA and NA, into subtypes (second paragraph of Introduction section).
The specification discloses in Example 1 that for improving stability of the H7 protein (i.e., the HA protein from the H7N9 subtype), the H3 protein from the H3N2 subtype was selected for recombination with the H7 protein since they are both belong to the Group II influenza viruses and the H3 protein (i.e., the HA protein from H3 influenza subtype virus) is phylogenetically related to the H7 protein (i.e., the HA protein from the H7 influenza subtype virus). A computational algorithm SCHEMA was used to identify fragments of proteins (also called protein blocks or domains) that can be recombined without disturbing the integrity of the three-dimensional structure of the protein of interest. The specification discloses that the selected H7 and H3 proteins have 49% identity to each other, and since the HA1 subunit of the HA protein is primarily responsible for sequence divergence and harbors most of the antigenic sites, the HA1 subunit of the H7 protein (SEQ ID NO: 1) and the HA1 subunit of the H3 protein (SEQ ID NO: 2) were collected for providing a total of non-identical amino acids for block assignment. Based upon analysis by said algorithm, it was decided to divide the HA1 subunits of the H7 and H3 proteins into six blocks (A-F), with divisions being non-contiguous along the peptide sequence. The amino acids in each block are assembled as integrated and structurally interacting domain, with the exception of block B which was divided into two sub-blocks. Each of the chimeric proteins was designed to only have one block swapped from the H3 protein and the rest of the protein originated from the H7 protein. The six individual clones are depicted in Table 1 of the specification (designated as rA to rF), with the corresponding amino acid sequences of the chimeric HA1 subunits rA to rF represented by SEQ ID NO: 3-8.
In Example 2, the chimeric HA1 subunits were fused with the HA2 subunit from the H7 protein at the C-termini since the bioactivity of the HA protein primarily relies on its trimeric conformation (and designated as FrA to FrF, respectively), with the parental constructs FH7 and FH3 using their original HA1 and HA2 sequences, respectively. The full-length sequences of the parental sequences and the chimeric constructs are represented by SEQ ID NO: 9-16, respectively.
The bioactivity of the proteins was assessed in Example 3 of the specification. Only chimeric proteins FrB (comprising SEQ ID NO: 4) and FrC (comprising SEQ ID NO: 5) possessed the correct conformation and function of HA after recombination, with FrB and FrC exhibiting significantly enhanced stability at 50 degrees C as compared to the parental FH7 protein (Example 4). (The other four FrA and FrD-FrF, comprising SEQ ID NO: 3 and 6-8 that have different combinations of HA1 blocks from H3 and H7 do not.) These two said chimeric HA FrB and FrC proteins can elicit H7-specific antibodies that are able to inhibit H7N9 viral infection in mice (Example 5). These two said chimeric proteins exhibit sialic acid receptor binding in vitro, as assayed by a hemagglutination assay (Fig. 8B).
Evidentiary reference Tsai et. al. (ACS Synthetic Biology, 9/30/19, 8: 2472-2482, IDS reference) recapitulates the disclosure of the instant specification enunciated above and adds “These results suggest that FrB and FrC (the same as are recited in the instant claims) preserved the conformation and function of HA after recombination, but the other four chimeric proteins showed defects in secretion and hemagglutination activity. The inability of these four chimeric Has [i.e., rA and rD-rF] to display hemagglutination activity indicates that they are either unable to bind the sialic acid receptor or cannot form an appropriate trimeric structure” (paragraph spanning columns 1-2 on page 2476). See entire reference.
Therefore, it appears that the instant specification does not adequately disclose the breadth of the chimeric HA protein and method of using it recited in the instant claims. In light of this, a skilled artisan would reasonably conclude that Applicant was not in possession of the genus of all such chimeric HA proteins and method of using them at the time the instant application was filed.
7. Claims 21-30 and 32-39 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The specification does not disclose how to make and/or use the instant invention over its full scope without undue experimentation:
a chimeric HA protein comprising an HA1 subunit and an HA2 subunit, wherein the HA 1 subunit is composed of a first domain derived from a parental HA1 subunit of a first subtype influenza virus and a second domain derived from a parental HA1 subunit of a second subtype influenza virus (as is recited in instant base claim 21), and including wherein
the first and second subtypes of influenza virus are independently select from the group consisting of those recited, provided the first and second subtypes are different (dependent claim 22);
the HA1 subunit has an amino acid identity less than 100% as compared with the parental HA1 subunit of the first subtype influenza virus (claim 23);
the HA1 subunit has an amino acid identity of at least 30% as compared with the parental HA1 subunit of the first subtype influenza virus (claim 24);
the HA1 subunit has an amino acid identity of between 70% and 95% as compared with the parental HA1 subunit of the first subtype as compared with the parental HA1 subunit of the first subtype influenza virus (claim 25);
the amino acid identity of the HA1 subunit compared to the parental HA1 subunit of the first subtype influenza virus is between 88% and 91% (claim 26);
the chimeric protein comprises at least one of the limitations recited in dependent claim 28 (amino acid residues in particular locations of the chimeric HA protein);
the first subtype influenza virus is an H7 subtype influenza virus (dependent claim 29);
the second subtype influenza virus is an H3 subtype influenza virus (dependent claim 30);
the HA1 subunit comprises an amino acid sequence that is one of SEQ ID NOs: 3 and 6-8 (corresponding to chimeric HA1 regions rA and rD-rF only that don’t have stability, sialic acid binding and/or trimerization, claim 32);
the HA2 subunit is an HA2 subunit of the first subtype influenza virus (dependent claim 33);
a vaccine composition comprising the HA protein of claim 21, wherein the chimeric HA protein is present in an amount effective in preventing influenza virus infection (claim 34), and further comprising an adjuvant (claim 35);
b) a method of including an immune response against an influenza virus in a subject in need thereof, comprising administering the vaccine composition according to claim 34 to the subject (as is recited in instant base claim 36), including wherein the influenza virus is H7N9 (Applicant’s elected species recited in dependent claim 37) or including wherein the HA1 subunit of the chimeric HA protein has an amino acid identity of at least 30% and less than 100% as compared with an HA1 subunit of the influenza virus (as is recited in dependent claim 38), including wherein the chimeric HA protein comprises an amino acid sequence that is one of SEQ ID NOs: 3 and 6-8 (corresponding to chimeric HA1 regions rA and rD-rF that don’t have stability, sialic acid binding and/or trimerization, claim 32).
The specification has not enabled the breadth of the claimed invention because the claims encompass: (a) a chimeric HA protein comprising an HA1 subunit and an HA2 subunit, wherein the said subunits are “derived from” a parental subunit of any influenza virus, including wherein the HA1 subunit has a percent identity with the parental subunit recited in the claims, and wherein the chimeric HA protein is a vaccine composition in an amount effective in preventing influenza virus infection (base claim 21 and its dependent claims), or (b) a method of inducing an immune response against an influenza virus in a subject in need thereof, comprising administering the vaccine composition according to claim 34, including wherein the chimeric HA protein comprises an amino acid sequence that is one of SEQ ID NO: 3 and 6-8 (corresponding to chimeric HA1 regions rA and rD-rF that don’t have stability, sialic acid binding and/or trimerization).
The state of the art is such that it is unpredictable in the absence of appropriate evidence whether the claimed compositions can be made and/or used over the full breadth of the claims without undue experimentation.
The specification discloses that “the term “chimeric HA protein,” “chimeric protein, “ or “chimeric subunit” as used herein refers to a single polypeptide unit that comprises at least two heterological domains joined by a peptide bond(s), wherein the different domains are not naturally occurring within the same polypeptide unit. As to the amino acid sequence of the chimeric protein, each heterological domain may correspond to non-continuous amino acids or a number of peptide fragments. These non-continuous amino acids and peptide fragments may assemble as an integrated and structurally interacting domain”(paragraph spanning pages 11-12).
The specification further discloses “The term “domain” or “protein block” as used herein refers to a set of at least one amino acid, at least one peptide, or a combination thereof in a protein. That is to say, a domain of a protein may include only one amino acid, a plurality of non-continuous amino acids, only one peptide, a plurality of peptide[s], or a combination thereof” (page 12 at lines 11-14).
The specification discloses “In one embodiment of the present disclosure, the second domain in the chimeric HA1 subunit is at least one portion of an HA structural region selected from the group consisting of a fusion peptide pocket, and HA1 region near the spring-loaded coiled-coil helix of the HA2 subunit, and HA1-HA1 interface, and an HA1-HA2 interface (page 14 at lines 10-13).
The specification discloses that the “HA protein of an influenza virus” is comprised of HA1 and HA2 subunits, of which the HA1 subunit contains a receptor binding site (RBS) for binding to sialic acid receptors, whereas the HA2 subunit contains a fusion peptide and TM domain that are responsible for trimerization (paragraph spanning pages 1-2).
The specification discloses “In one embodiment of the present disclosure, the second domain in the chimeric HA1 subunit is at least one portion of an HA structural region selected from the group consisting of a fusion peptide pocket, and HA1 region near the spring-loaded coiled-coil helix of the HA2 subunit, and HA1-HA1 interface, and an HA1-HA2 interface (page 14 at lines 10-13).
The specification discloses that in some embodiments of the present disclosure, the first and second subtype influenza viruses may be independently selected from Group I influenza viruses such as H1, H2, H5, H6, H8, H9, H11-H13 and H16-H18 or Group II influenza viruses such as H3, H4, H7, H10, H14, and H15 subtype influenza viruses (page 11 at lines 11-18).
The specification does not disclose a limiting definition for “derived from”.
Evidentiary reference Sautto et al. (Virol. Journal, 2018, 15(17): 1-12, IDS reference) teaches that within a subtype, there is up to about 15% amino acid sequence diversity, whereas HA proteins between subtypes have 40% or 60% sequence diversity, which highlight the great hypervariable nature of these viral proteins (page 2 at column 2 at the first full paragraph). Sautto et al. further teach that influenza A viruses circulate in many avian species and infect several mammalian species including humans, wherein influenza B viruses infect only humans, influenza C viruses infect humans and pigs, and influenza D viruses primarily infect cattle (first paragraph of Introduction section on page 2). Sautto et al. teach that each influenza virus is further classified on the basis of the surface glycoproteins HA and NA, into subtypes (second paragraph of Introduction section).
The specification discloses in Example 1 that for improving stability of the H7 protein (i.e., the HA protein from the H7N9 subtype), the H3 protein from the H3N2 subtype was selected for recombination with the H7 protein since they are both belong to the Group II influenza viruses and the H3 protein (i.e., the HA protein from H3 influenza subtype virus) is phylogenetically related to the H7 protein (i.e., the HA protein from the H7 influenza subtype virus). A computational algorithm SCHEMA was used to identify fragments of proteins (also called protein blocks or domains) that can be recombined without disturbing the integrity of the three-dimensional structure of the protein of interest. The specification discloses that the selected H7 and H3 proteins have 49% identity to each other, and since the HA1 subunit of the HA protein is primarily responsible for sequence divergence and harbors most of the antigenic sites, the HA1 subunit of the H7 protein (SEQ ID NO: 1) and the HA1 subunit of the H3 protein (SEQ ID NO: 2) were collected for providing a total of non-identical amino acids for block assignment. Based upon analysis by said algorithm, it was decided to divide the HA1 subunits of the H7 and H3 proteins into six blocks (A-F), with divisions being non-contiguous along the peptide sequence. The amino acids in each block are assembled as integrated and structurally interacting domain, with the exception of block B which was divided into two sub-blocks. Each of the chimeric proteins was designed to only have one block swapped from the H3 protein and the rest of the protein originated from the H7 protein. The six individual clones are depicted in Table 1 of the specification (designated as rA to rF), with the corresponding amino acid sequences of the chimeric HA1 subunits rA to rF represented by SEQ ID NO: 3-8.
In Example 2, the chimeric HA1 subunits were fused with the HA2 subunit from the H7 protein at the C-termini since the bioactivity of the HA protein primarily relies on its trimeric conformation (and designated as FrA to FrF, respectively), with the parental constructs FH7 and FH3 using their original HA1 and HA2 sequences, respectively. The full-length sequences of the parental sequences and the chimeric constructs are represented by SEQ ID NO: 9-16, respectively.
The bioactivity of the proteins was assessed in Example 3 of the specification. Only chimeric proteins FrB and FrC (out of the FrB-FrF chimeric proteins) possessed the correct conformation and function of HA after recombination, with FrB and FrC exhibiting significantly enhanced stability at 50 degrees C as compared to the parental FH7 protein (Example 4). These said chimeric HA proteins can elicit H7-specific antibodies that are able to inhibit H7N9 viral infection in mice (Example 5). These two said chimeric proteins exhibit sialic acid receptor binding in vitro, as assayed by a hemagglutination assay (Fig. 8B).
Evidentiary reference Tsai et. al. (ACS Synthetic Biology, 9/30/19, 8: 2472-2482, IDS reference) recapitulates the disclosure of the instant specification enunciated above and adds “These results suggest that FrB and FrC (the same as are recited in the instant claims) preserved the conformation and function of HA after recombination, but the other four chimeric proteins showed defects in secretion and hemagglutination activity. The inability of these four chimeric Has [i.e., rA and rD-rF] to display hemagglutination activity indicates that they are either unable to bind the sialic acid receptor or cannot form an appropriate trimeric structure” (paragraph spanning columns 1-2 on page 2476).
The specification does not disclose any working examples of chimeric HA protein comprising HA1 and HA2 subunits derived from any other subtypes of influenza virus.
There is insufficient guidance in the specification as to how to make and/or use the instant invention. Undue experimentation would be required of one skilled in the art to practice the instant invention. See In re Wands 8 USPQ2d 1400 (CAFC 1988).
8. 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.
9. Claim 28 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 28 is indefinite in the recitation of the recited amino acid residues with no recitation to a sequence identifier. Claim 28 is also indefinite in the recitation of HA-HA1 or HA1-HA2 interface or the fusion peptide pocket because it is not clear what is meant. The specification discloses at page 14, lines 14-19, that a fusion peptide pocket is a region near the “F domain” of the HA1 subunit which surrounds the fusion peptide, that an HA1-HA2 interface is a region of the interface between the HA1 receptor-binding domain protomers, and that an HA1-HA1 interface is a region between the receptor-binding domain, esterase subdomain, helix C, and loop B. The specification discloses, referring to Figs 4A-4D models that detail the residues recited in claim 28, but with specific position numbers relative to “FB” (corresponds to the full length construct with the chimeric HA1 domain that corresponds to ”rB” and the H7 HA2 parental domain) or to the FrC chimeric protein comprising the rC HA1 domain and the parental H7 HA2 domain). The specification also discloses non-limiting examples of fusion peptide pocket residues, HA1 region near spring loaded coiled-coil, HA1-HA1 interface of SEQ ID NO: 12 or the HA1-HA2 interface relative to SEQ ID NO: 13 (page at lines 8-16).
10. 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.
11. For the purpose of prior art rejections, the filing date of the instant claim 37 is deemed to be the filing date of PCT/US2020/051395, i.e., 9/18/20, as provisional applications 62903011 and 62904014 do not support the claimed limitations of the instant application. The provisional applications do not provide support for the full complement of recited influenza viruses.
For the purpose of prior art rejections, the filing date of the instant claims 21-29, 32-36, 38 and 39 is deemed to be the filing date of provisional application 62/904,014, i.e., 9/23/19.
12. The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
13. Claims 21-26, 29-30 and 34-38 are rejected under 35 U.S.C. 102(a)(i) as being anticipated by KR 10-1835989 B1 (3/8/2018, IDS reference) as evidenced by Scribbr (2025, 1 page).
Independent claim 21 recites: A chimeric hemaglutinin (HA) protein comprising an HA11 subunit and an HA2 subunit, wherein the HA1 subunit is composed of a first domain derived from a parental HA1 subunit of a first subtype influenza virus and a second domain derived from a parental HA1 subunit of a second subtype influenza virus.
Independent claim 36 recites: A method of inducing an immune response against an influenza virus in a subject in need thereof, comprising administering the vaccine composition according to claim 34 to the subject.
Claim interpretation: There is no limiting definition for the limitation “derived from” recited in instant base claim 21. Instant base claim 21 recites the open transitional phrases “comprising” and “is composed of”, opening the chimeric protein as well as the HA1 subunit to comprise more than one domain derived from different subtypes of influenza virus and not limited to just a first and second different subtype. The specification discloses that in various [non-limiting] embodiments, a subject may be a vertebrate, a mammal or human (page 6 at lines12-14).
KR10-1835989 B1 teaches a chimeric protein/vaccine composition thereof for preventing or treating an influenza infection, the composition comprising an influenza HA1 and an HA2 subunit, wherein the said subunits are derived from multiple different subtypes of influenza viruses to provide cross-protection against the H3 (H3N2) and H7 (H7N9) subtypes of influenza viruses. KR10-1835989 B1 teaches a vaccine composition administered to a subject and having neutralizing antibody effects (see abstract figure, [0055], [0077], “<120>” and Figures immediately preceding the section labeled “<110>”.
Evidentiary reference Scribbr teaches that the passive phrasing “is composed of” means the same thing as “comprises”.
Although the art reference does not explicitly recite the percent amino acid identity of the chimeric HA1 subunit with the parental subunit(s) or inclusion of an adjuvant in the administered composition, it does teach the multiple subunits derived from multiple different subtypes of influenza virus and that the administered composition was affective for preventing influenza infection. Therefore, with regard to the limitations reciting percent amino acid identity and adjuvant, the claimed chimeric protein/vaccine thereof and method of inducing an immune response appears to be the same as the product and method of the prior art absent a showing of differences. Since the Patent Office does not have the facilities for examining and comparing the product and method of the instant invention to those of the prior art, the burden is on Applicant to show a distinction between the product and method of the instant invention and that of the prior art. See In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977).
14. 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.
15. Claims 21-26, 29-30 and 34-38 are rejected under 35 U.S.C. 103 as being unpatentable over KR 10-1835989 B1 (3/8/2018, IDS reference) as evidenced by Scribbr (2025, 1 page, worldwideweb at scribbr.com) in view of Perrie et al. (Int. J. Pharm. 2008, 364: 272-280).
Independent claim 21 recites: A chimeric hemaglutinin (HA) protein comprising an HA11 subunit and an HA2 subunit, wherein the HA1 subunit is composed of a first domain derived from a parental HA1 subunit of a first subtype influenza virus and a second domain derived from a parental HA1 subunit of a second subtype influenza virus.
Independent claim 36 recites: A method of inducing an immune response against an influenza virus in a subject in need thereof, comprising administering the vaccine composition according to claim 34 to the subject.
Claim interpretation: There is no limiting definition for the limitation “derived from” recited in instant base claim 21. Instant base claim 21 recites the open transitional phrases “comprising” and “is composed of”, opening the chimeric protein as well as the HA1 subunit to comprise more than one domain derived from different subtypes of influenza virus and not limited to just a first and second different subtype. The specification discloses that in various [non-limiting] embodiments, a subject may be a vertebrate, a mammal or human (page 6 at lines12-14).
KR10-1835989 B1 teaches a chimeric protein/vaccine composition thereof for preventing or treating an influenza infection, the composition comprising an influenza HA1 and an HA2 subunit, wherein the said subunits are derived from multiple different subtypes of influenza viruses to provide cross-protection against the H3 (H3N2) and H7 (H7N9) subtypes of influenza viruses. KR10-1835989 B1 teaches a vaccine composition administered to a subject and having neutralizing antibody effects (see abstract figure, [0055], [0077], “<120>” and Figures immediately preceding the section labeled “<110>”.
Evidentiary reference Scribbr teaches that the passive phrasing “is composed of” means the same thing as “comprises”.
Although KR10-1835989 B1 teaches that the composition comprising the chimeric protein is effective when administered, it does not explicitly teach wherein the vaccine composition also comprises an adjuvant.
Perrie et al. teach that the immunogenicity of protein subunit vaccines which is normally low is increase by the use of adjuvants (see entire reference, especially abstract).
It would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have included an adjuvant in the administered composition.
One of ordinary skill in the art would have been motivated to do this, and with a reasonable expectation of success in doing so, to increase the immunogenicity of the chimeric protein vaccine composition taught by the primary art reference.
Although the art reference does not explicitly recite the percent amino acid identity of the chimeric HA1 subunit with the parental subunit(s), it does teach the multiple subunits derived from multiple different subtypes of influenza viruses. Therefore, with regard to the limitations reciting percent amino acid identity, the claimed chimeric protein/vaccine thereof and method of inducing an immune response appears to be similar to the product and method of the prior art absent a showing of unobvious differences. Since the Patent Office does not have the facilities for examining and comparing the product and method of the instant invention to those of the prior art, the burden is on Applicant to show an unobvious distinction between the product and method of the instant invention and that of the prior art. See In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977).
16. No claim is allowed.
17. SEQ ID NO: 3-8 are free of the prior art.
18. Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARIANNE DIBRINO whose telephone number is (571)272-0842. The examiner can normally be reached on M, T, Th, F.
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/Marianne DiBrino/
Marianne DiBrino, Ph.D.
Patent Examiner
Group 1640
Technology Center 1600
/MICHAEL SZPERKA/Primary Examiner, Art Unit 1641