engthNotice of Pre–AIA or AIA Status
1. 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
Status of Claims
2. Applicant’s election without traverse of Group I for claims 1 – 10 and the species of the Dengue vaccine heavy chain (DeNHC), drawn to SEQ ID NO: 8 in claims 1 and 3, and SEQ ID NO: 2 in claim 2 to obtain SEQ ID NO: 9 in claim 2 in the reply filed on 12/20/2025 is acknowledged. Claims 11 – 20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/20/2025. Claims 1 – 10 are pending in this application and are under examination.
Priority
3. The instant application does not claim priority to any patent applications. Thus, the U.S. effective filing date is 06/20/2023 for the claims presently under examination.
Information Disclosure Statement
4. No information disclosure statement (IDS) was present at the time of this office action. 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. Applicant is reminded of the duty to disclose information to the Office which is material to patentability as defined in 37 CFR 1.56. This includes a list of all patents, publications, or other information that should be considered by the Office pursuant to 37 CFR 1.98(b). See MPEP § 609.
Specification
5. The disclosure is objected to because of the following informalities:
There is a missing comma after DENV–3 on page 5, paragraph 0019;
Page 5, paragraph 0020 recites the phrase “one or more of the nucleic acid sequences encoded by SEQ ID NOs: 4 – 9”. However, SEQ ID NOs: 5, 7, and 9 are amino acid sequences, not nucleic acid sequences;
Page 11, paragraph 0069 recites the phrase “[T]he amino acid sequence of the HCT (SEQ ID NO: 2) was used as a backbone. LCT backbone was translated…”. It is unclear if the LCT was a typographical error, or if the LCT backbone is intended to be different from the HCT backbone described in the previous sentence;
The sequence listed on page 13, paragraph 0079 is improper. The sequence should be listed as “SEQ ID NO: 8”;
The sequence listing of SEQ ID NOs: 4,5: 6,7: and 8,9 on page 13, paragraphs 0081 and 0082 is improper. More appropriate language would be “SEQ ID NOs: 4 – 9”;
The sequence listing of SEQ ID NOs: 4, 5; 6, 7; 8 and 9 on page 14, paragraph 0092 is improper. More appropriate language would be “SEQ ID NOs: 4 – 9”.
Appropriate correction is required.
6. The use of the terms Bio–Rad™ on page 12; Trans–Blot® Turbo™ Transfer System on page 12; Tween 20™ on page 12; SVMTrip™ on page 13; and possibly others in the specification, which are trade names or a marks used in commerce, have been noted in this application. The terms should be accompanied by the generic terminology; furthermore, the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, ℠, or ® following the terms. Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks. Applicant is required to properly annotate all trade names and/or marks present in the specification.
7. The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim Objections
8. Claims 1 objected to because of the following informalities:
In claim 1, line 11, the acronym “DENV–1” is recited, but not defined in the claim. An acronym should be defined the first time it appears in the claims. For the purposes of examination, “DENV–1” is interpreted to mean “Dengue virus serotype 1”, as defined in the specifications;
In claim 1, line 11, the acronym “DENV–2” is recited, but not defined in the claim. An acronym should be defined the first time it appears in the claims. For the purposes of examination, “DENV–2” is interpreted to mean “Dengue virus serotype 2”, as defined in the specifications;
In claim 1, line 11, the acronym “DENV–3” is recited, but not defined in the claim. An acronym should be defined the first time it appears in the claims. For the purposes of examination, “DENV–3” is interpreted to mean “Dengue virus serotype 3”, as defined in the specifications;
In claim 1, line 12, the acronym “DENV–4” is recited, but not defined in the claim. An acronym should be defined the first time it appears in the claims. For the purposes of examination, “DENV–4” is interpreted to mean “Dengue virus serotype 4”, as defined in the specifications;
In claim 4, line 2, the phrase “mammalian” is grammatically incorrect. The phrase should either be “mammals” or “mammalian cells”;
In claim 5, line 2, there is an extra space in between Clostridium botulinum and the comma that should be removed;
In claim 10, line 3, there is a typographical error, wherein “sub lingual” should read “sublingual”.
Appropriate correction is required.
Claim Rejections – 35 USC § 112
35 USC § 112(b)
9. 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.
10. Claims 1 – 10 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.
11. The term “effective” in claim 1 is a relative term which renders the claim indefinite. The term “effective” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. While paragraph 0066 on page 10 of the specification defines an effective immune response as prevention of infection and/or reduction in symptoms upon infection, it does not define the degree of reduction that qualifies as an “effective” immune response – i.e., how reduced do the symptoms need to be for an immune response to be considered “effective”? What is the threshold for the prevention of infection? The claims that recite “effective” are thus rendered indefinite. It is suggested that every iteration of the term be removed in its current usage.
12. Claim 1 recites the limitation "...one or more amino acid sequences encoded by...a vector comprising a nucleic acid sequence..." in lines 2, 3, 8, and 9. Based on the specification, it appears that SEQ ID NO: 8 encodes for SEQ ID NO: 9. The specification describes SEQ ID NO: 8 as the nucleotide sequence of DeNHC (page 9, paragraph 0051), whereas SEQ ID NO: 9 is the amino acid sequence of the DeNHC (page 9, paragraph 0052). A translation of SEQ ID NO: 8 to an amino acid sequence has revealed that the amino acid sequence of SEQ ID NO: 9 appears to be encoded by the nucleotide sequence of SEQ ID NO: 8 (see the percent identities reproduced below on the top left). However, this is not how the claim is read. Furthermore, the claim recites that the one or more amino acid sequences are encoded by SEQ ID NOs: 4, 6, and/or 8. It is unclear if the amino acid sequence encoded by these vectors is comprised of the entire sequence, i.e., the full-length, or just any sequence encoded thereby that falls within the full-length, i.e., the partial sequence. Thus, the presence of multiple very different interpretations of the same claim language renders the claim indefinite. Claims 2 – 10 are rejected by virtue of their dependency on claim 1. In the interest of compact prosecution, it will be interpreted that SEQ ID NO: 8 encodes for SEQ ID NO: 9, as described in the specification (page 4, paragraph 0014; page 9, paragraphs 0051 and 0052). However, appropriate correction is required.
13. Claim 2 recites the limitation "...an amino acid sequence of...to obtain the one or more amino acid sequences encoded..." in lines 2 and 3. SEQ ID NO: 2 is described in the specification (page 9, paragraph 0045) as the amino acid sequence of the heavy chain domain of detoxified recombinant tetanus neurotoxin (DrTeNT), whereas SEQ ID NO: 9 is described as the amino acid sequence of the DeNHC (page 9, paragraph 0052). One amino acid sequence cannot encode for another amino acid sequence. Additionally, the sequences of SEQ ID NOs: 2 and 9 do not have 100% similarity, but rather 81.6% similarity, as seen in the percent identities reproduced above on the bottom left. Moreover, SEQ ID NOs: 1 and 3, which are also recited in the claim, only have 22.6% and 75.8% similarity, respectively, to SEQ ID NO: 9 (see the percent identities reproduced above on the top right and bottom right, correspondingly). It is unclear how the amino acid sequence of SEQ ID NO: 9 is obtained from the amino acid sequence of SEQ ID NOs: 1, 2, or 3, as recited in the claim. Moreover, it is unclear how any iteration/mutation can maintain at least 90% sequence identity to the elected species of SEQ ID NO: 2 while leading to a sequence that has at least 90% sequence identity to SEQ ID NO: 9. Mutating 10% of SEQ ID NO: 2 would only change 96 residues. Even if these 96 residues were perfectly mutated to match SEQ ID NO: 9, it still would not be enough to yield a peptide of at least 90% identity as SEQ ID NO: 9 is longer than SEQ ID NO: 2 at 1173 residues, wherein 117 residues must be perfectly matched. Another product or variant of SEQ ID NO: 2 would need to be added, wherein this product would be a different protein with more similarity to SEQ ID NO: 9. However, no such limitation is recited. Thus, the claim is rendered indefinite as it is unclear how including SEQ ID NO: 2, variant thereof, or other product, would provide a peptide with at least 90% sequence identity to SEQ ID NO: 9 in the given composition. In the interest of compact prosecution, it will be understood that SEQ ID NO: 9 is either embedded or chemically attached to the sequence encoded by SEQ ID NO: 2, as disclosed in the specification (pages 5 and 6, paragraph 0020), but encoded by SEQ ID NO: 8 instead of SEQ ID NO: 2, as discussed above in paragraph 12.
14. It is noted that any interpretation of the claims set forth above does not relieve Applicant of the responsibility of responding to this Office Action. If the actual interpretation of the claims is different than that posited by the Examiner, additional rejection(s) and art may be applied in a subsequent Office Action.
35 USC § 112(a)
15. 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.
35 USC § 112(a) – Written Description
16. Claims 1 – 10 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 purpose of [the written description requirement] is to ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification"); LizardTech Inc. v. Earth Resource Mapping Inc., 424 F.3d 1336, 1345, 76 USPQ2d 1724, 1732 (Fed. Cir. 2005). This requirement is separate and distinct from the enablement requirement. To satisfy the written description requirement for a claimed genus, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention at the time of filing. See In re Reiffin v. Microsoft Corp., 214 F.3d 1342, 1345, 54 USPQ2d 1915, 1917 (Fed. Cir. 2000). “Even if a claim is supported by the specification, the language of the specification, to the extent possible, must describe the claimed invention so that one skilled in the art can recognize what is claimed. The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement.” See In re Enzo Biochem, Inc. v. Gen–Probe, Inc., 323 F.3d 956, 968, 63 USPQ2d 1609, 1616 (Fed. Cir. 2002). See also MPEP § 2163.
The written description requirement may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or 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. See In re University of California v. Eli Lilly & Co., 119 F.3d 1559, 1566, 43 USPQ2d 1398, 1404 (Fed. Cir. 1997); and Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337, 2021 USPQ2d 893 (Fed. Cir. 2021).
A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, the applicant must describe a sufficient variety of species to reflect the variation within the genus. See In re AbbVie Deutschland GMBH v. Janssen Biotech, 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]." See In re Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004). "A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed." See In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004).
The Federal Circuit has clarified the application of the written description requirement to inventions in the field of biotechnology. The Court stated that a written description of an invention requires a precise definition, one that defines the structural features of the chemical genus that distinguishes it from other chemical structures. A definition by function does not suffice to define the genus because it is only an indication of what the genus does, rather than what it is. This is because functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. Further, the Court held that to adequately describe a claimed genus, an applicant must describe a representative number of species of the claimed genus, and that one of skill in the art should be able to “visualize or recognize the identity of the members of the genus.” The description needed to satisfy the written description varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology. See In re University of California v. Eli Lilly and Co., 119 F.3d 1559, 1568, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997); In re AbbVie Deutschland GMBH v. Janssen Biotech, 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014); In re Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 94 USPQ2d 1161 (Fed. Cir. 2010); and In re Capon v. Eshhar, 418 F.3d at 1357, 76 USPQ2d at 1084.
Claims 1 – 10 are drawn to a pharmaceutical composition for eliciting an effective immune response in a patient against two or more Dengue virus serotypes comprising an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 9, as disclosed in claim 2, that is encoded by a nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 8, as stated in claims 1 and 3, and embedded in or chemically attached to an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 2, as required in claim 2. Claims 4 – 10 add additional modifications to the sequence disclosed in claim 1, including the expression system in claim 4, wherein expression occurs in one or more of bacteria, yeast, insects, mammalian cells, or any other appropriate expression system.
SEQ ID NO: 2 is 960 amino acids in length; SEQ ID NO: 8 is 3476 nucleotides in length; and SEQ ID NO: 9 is 1173 amino acids in length. The claims encompass any sequence having at least 90% sequence identity to SEQ ID NOs: 2 and 9 and at least 95% sequence identity to SEQ ID NO: 8. An amino acid sequence sharing only 90% identity relative to SEQ ID NOs: 2 could have anywhere from 1 to 96 substitutions, deletions, additions, or any combination thereof, along the length of SEQ ID NOs: 2, correspondingly, which corresponds to a massive genus of 2096 = 7.9 x 10124 sequences with respect to SEQ ID NO: 2 alone. The same logic applies to SEQ ID NO: 9, wherein 90% sequence identity would equate to 20117 = 1.7 x 10152 possible sequence combinations in the genus; and SEQ ID NO: 8, wherein 95% sequence identity would equate to 4174 = 5.7 x 10104 possible combinations. Moreover, the nucleotide sequence of SEQ ID NO: 8 must encode for the amino acid sequence of SEQ ID NO: 9, which would be uncommon with such a large genus. Additionally, the claims require an expression system that can be bacteria, yeast, insects, mammalian cells, or any other appropriate expression system. There are numerous bacteria strains that can be employed for expression, i.e., Escherichia coli BL21(de3), E. coli BL21(de3)pLysS, E. coli BL21–CodonPlus, to name a few, creating a large range of possibilities for the bacteria genus alone. This genus grows exponentially larger when expanded to yeast, insects, and mammalian cells, which in themselves all have numerous options that can be employed. In general, this creates an enormous breadth of potential expression systems that becomes innumerable when coupled with the massive genera of sequences.
When there is substantial variation within the genus, as here, one must describe a sufficient variety of species to reflect the variation within the genus to provide a “representative number” of species. The claims are drawn to several genera that are comprised of innumerable sequences and expression systems, yet, the specification has only adequately described, and successfully reduced to practice, one construct in one mammalian cell line. The specification only provides adequate written description for construct II, which is expressed in Chinese Hamster Ovary (CHO) cells with kanamycin and puromycin as the selection marker (page 11, paragraph 0069), wherein the (1) nucleotide sequence drawn to SEQ ID NO: 8 that encodes for (2) SEQ ID NO: 9 is inserted into the (3) heavy chain domain of DrTeNT drawn to SEQ ID NO: 2, which was used as a backbone. This is not representative of the extremely large genus of sequences and expression systems claimed. One of ordinary skill in the art cannot conclude that Applicant was in possession of the trillions of sequences encompassed by the disclosed genera. Absent the construct II in CHO cells, the skilled artisan generally would not be able to visualize or otherwise predict, a priori, each individual sequence or the expression system utilized. Thus, it is clear that the breadth of the recited genera in the claims far overreaches the Applicant’s contribution.
In the absence of a representative number of examples, the specification must at least describe the structural features that are required for the claim function. In the instant case, the specification should explain how expression of the vector elicits an effective immune response in a patient. However, the specification fails to describe any substantive structural limitations as to establish a structure–function relationship with respect to an immune response against two more Dengue virus serotypes. At best, the specification contemplates the use of BLAST to identify functional homologs based on sequence homology. However, this is not sufficient to describe members of the claimed genus because such methods access online databases that are continually being updated as sequencing technology improves. As a result, they are not a static source of information. Therefore, one having ordinary skill in the art would readily appreciate that relying on a non–patent source that is continuously subject to change as a means to identify members of the claimed genus does not sufficiently meet the written description requirement.
The art teaches that protein chemistry is an extremely unpredictable area of biotechnology, wherein even a single substitution can change the biological property of a peptide. For example, Burgess, W. H., et. al. (Possible dissociation of the heparin–binding and mitogenic activities of heparin–binding (acidic fibroblast) growth factor–1 from its receptor–binding activities by site–directed mutagenesis of a single lysine residue. The Journal of cell biology, 111(5 Pt 1), 2129–2138; Published 11/1990) teaches that replacement of a single lysine residue by a glutamic acid residue can lead to substantial loss of receptor binding and biological activity of a protein (page 2129; abstract). Moreover, Friedberg, I. (Automated protein function prediction––the genomic challenge. Briefings in bioinformatics, 7(3), 225–242; Published 01/25/2006) teaches that homology–based transfer is not reliable for functional annotation even with high alignment percentages (page 227, second column). Friedberg, I. also teaches that identification of functionally significant sub–regions is critical to functional annotation, and that often addition, deletion, or re–shuffling of domains can lead to errors in annotation (page 227, second column; page 228, first paragraph). Furthermore, Friedberg, I. teaches that as databased and, thus, diversity of sequences, get larger, sequence–based tools are not sensitive enough to identify functional protein similarity (page 228, first full paragraph). Thornton, J. (Structural genomics takes off. Trends in biochemical sciences, 26(2), 88–89; Published 02/01/2001) teaches that the same protein structure is often seen in apparently different homologous families with different functions. Thornton, J. further describes examples of little correlation between specific binding function and overall protein structure (page 992, right column, lines 2 – 10). Mancia, F., et. al. (Optimization of protein production in mammalian cells with a coexpressed fluorescent marker. Structure, 12(8), 1355–1360; Published 08/2004) teaches that protein expression can vary widely depending on the expression system utilized, i.e., mammalian cells versus bacteria (page 1355; abstract and introduction). Thus, when taken with the teachings of Burgess, W. H., et. al., Friedberg, I., Thornton, J., and Mancia, F., et. al., one having ordinary skill in the art would readily appreciate that sequence homology alone cannot serve as the basis to describe members of the genus that have the recited function and their expression would be a result effective parameter requiring optimization in each type of expression system.
In summary, these examples teach that the biological function of peptide variants is unpredictable because even a single mutation can abolish activity or give a different function. Moreover, expression of the peptide can vary based on the expression system employed. Thus, while Applicant has described a species within the genus recited, and the art may provide more, each genus is very large and would encompass peptide structures that cannot be visualized from the prior art or instant disclosure. One having ordinary skill in the art cannot determine the structures encompassed by the claimed genera. Thus, the described species cannot be considered representative of the entire recited genus.
Overall, the claims as currently written are not adequately described and one of ordinary skill in that art would readily appreciate that Applicant was not in possession of the claimed genera at the time of filing. At present, it is recommended that the claims remove the recitation of “at least 90%” in claims 1 and 2 and “at least 95%” in claim 3, wherein the SEQ ID NOs disclosed are the single genera. Additionally, it is suggested that claim 4 be amended to include the expression system Applicant had in their possession at the time of filing.
35 USC § 112(a) – Enablement
17. Claims 1 – 10 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the tested protein variants shown to function, including all epitopes tested and shown to produce neutralizing antibodies, does not reasonably provide enablement for merely any protein variant, specifically those that cause an immune response that will generate neutralizing antibodies. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
18. In order to determine compliance with the enablement requirement of 35 U.S.C. 112(a), the Federal Circuit has developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors, to assess whether any necessary experimentation required by the specification is "reasonable" or is "undue." The factors considered include (A) the breadth of the claims; (B) the nature of the invention; (C) the state of the prior art; (D) the level of one of ordinary skill in the art; (E) the level of predictability in the art; (F) the amount of direction provided by the inventor; (G) the existence of working examples; and (H) the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Breadth of the claims and nature of the invention: Claim 1, and claims 2 – 10 by virtue of their dependency on claim 1, of the claimed invention are drawn to a pharmaceutical composition for eliciting an effective immune response, i.e., a neutralizing antibody titer, in a patient against two or more Dengue virus serotypes, comprising one or more amino acid sequences encoded by a vector comprising a nucleic acid sequence with at least 90% sequence identity to SEQ ID NO: 8.
Further limitations to the method include the sequence for the amino acid encoded by SEQ ID NO: 9, the expression system, a list of adjuvants to be combined with the vector, the type of patient, the form of the composition, i.e., protein, DNA, or plasmid, and the route of administration, including intraperitoneal (IP), subcutaneous (SubQ), intramuscular (IM), oral, buccal, sublingual, nasal, or topical.
State of the prior art and unpredictability in the art: According to the specification of the claimed
invention, there are no dengue vaccines or antiviral drugs against the four serotypes of Dengue that are available for public use without safety concerns (page 2, paragraph 0005). The specification also discloses that there is conflicting knowledge as to whether or not an immunoglobulin (Ig)-like C terminal domain (EDIII) based vaccine can evoke protective neutralizing antibodies, wherein neutralizing epitopes of EDIII have been identified, but the effectiveness is questionable (page 3, paragraph 0007).
However, in the art, there are two live attenuated tetravalent Dengue vaccines are currently on the market: one from Takeda™, known as Qdenga® (TAK–003), and one from Sanofi, known as Dengvaxia®, as evidenced by Angelin, M., et. al. (Qdenga® – A promising dengue fever vaccine; can it be recommended to non–immune travelers?. Travel medicine and infectious disease, 54, 102598; Published 06/02/2023), hereby Angelin. Angelin teaches that Dengvaxia® is based on a yellow fever backbone and was introduced to the public in 2015 (page 1, introduction, left column). However, it is further taught that Dengvaxia® had an efficacy of 60% and safety concerns, wherein those vaccinated with it were at increased risk for virologically confirmed dengue fever (VCD) over the placebo group (page 1, introduction, right column). Angelin goes on to teach that as a result of these safety concerns, Dengvaxia® is now limited to individuals with previous dengue fever and not for vaccination of the general public (page 1, introduction, right column). On the other hand, Angelin teaches that Qdenga® is based on a DENV2 backbone that is administered as a SubQ injection with an efficacy of 80% (page 2, left column). It is further taught that Qdenga® induces antibody responses against all four serotypes of dengue and has been recommended for general public usage as a travel vaccine (page 2, right column). However, Angelin does not teach alternative routes of administration for vaccination. In summary, Angelin teaches two tetravalent Dengue vaccines: one of which, Qdenga®, is presently available to the public to protect against Dengue infection.
Further in the art, Kwon, K. M., et. al. (Microneedles: quick and easy delivery methods of vaccines. Clinical and experimental vaccine research, 6(2), 156–159; Published 07/26/2017) teaches that vaccine administration commonly occurs via intradermal, IM, SubQ, and oral routes (page 156, second paragraph). It is further taught that methods for needle–free vaccination via mucosal surface vaccination, including intranasal and sublingual routes, have been proposed and are currently being investigated, but the safety and efficacy of these methods in comparison to traditional vaccination methods is unknown (page 157, left column, first paragraph).
Moreover, Modis, Y., et. al. (Variable Surface Epitopes in the Crystal Structure of Dengue Virus Type 3 Envelope Glycoprotein. Journal of virology, 79(2), 1223–1231; Published 01/15/2005) teaches that there are nonneutralizing and neutralizing antibodies against Dengue virus that recognize different epitopes (page 1223, abstract). It is further taught that neutralizing antibodies are often located within domain III of the Dengue virus envelope glycoprotein (page 1224, left column). Page 1227 teaches that the most well-characterized antibodies for EDIII wherein the epitopes elicit both neutralizing and nonneutralizing antibodies. Importantly, it is not clear from the prior art or instant specification that any Dengue virus epitope/antigen in the elected immunogen elicits neutralizing antibodies and so would be capable of meeting the claim limitations to their full scopes.
To summarize, the prior art, as of 06/20/2023, does not provide evidence for safe vaccination via IP, oral, buccal, sublingual, or topical routes, but does teach the existence of a tetravalent vaccine that elicits a neutralizing response for all four serotypes of Dengue virus and is safe for usage by the general public wherein there are some epitopes of the EDIII that induce protective immunity against Dengue virus. The prior art is silent as to the immunogen of instant claims however.
Those with relevant skill in the art: The level of skill in the art is that of Ph.D.–level scientists and
medical doctors (D.O. and/or M.D.).
Amount of direction and existence of working examples: The instant application teaches one working example, which does not represent an example for the trillions of sequences described above in paragraph 16; expression in yeast, bacteria, or insects; administration of the vaccine; or neutralizing antibodies elicited by the composition. Thus, the instant application offers no reasonable guidance or direction to use the claimed method for eliciting an effective immune response in a patient against two or more Dengue virus serotypes. G – g
The closest working example is in paragraphs 0069 – 0076 on pages 11 – 13, hereby referred to as example 1. Example 1 teaches that construct II was created by embedding the DeNHC, as indicated by nucleotide sequence SEQ ID NO: 8 that encodes for SEQ ID NO: 9, into the amino acid sequence of the HCT, as encoded by SEQ ID NO: 2, which serves as the backbone. It is further taught that SEQ ID NO: 8 has four epitopes of DENV1, three each of DENV2 and DENV3, and two of DENV4, and is optimized for CHO cells with kanamycin and puromycin as the selection marker. Additionally, the expression and purification of construct II is taught by example 1. It is further disclosed that epitopes for Dengue virus serotypes 1 – 4 are selected and inserted into the vector.
The instant application has no examples of expressing the vectors in bacteria, yeast, or insects, or administering the vaccine. There is no guidance as to what nucleotides and associated amino acids may be changed with SEQ ID NOs: 8 and 9 to adhere to the 95% and 90% sequence identity, correspondingly, without losing the immunization feature of the composition. The safety and efficacy of the composition is not disclosed. Moreover, whether or not the inserted epitopes are directed to those responsible for neutralizing antibodies is not defined.
Quantity of experimentation needed: The recitation of the percent identities in the claims would require undue experimentation due to the unpredictability of protein mutations and their impacts on structure and/or function. It is unpredictable as to which nucleotides/amino acids could be removed and which could be added. For example, Burgess, W. H., et. al. (Possible dissociation of the heparin–binding and mitogenic activities of heparin–binding (acidic fibroblast) growth factor–1 from its receptor–binding activities by site–directed mutagenesis of a single lysine residue. The Journal of cell biology, 111(5 Pt 1), 2129–2138; Published 11/1990) teaches that site-directed mutagenesis of a single lysine residue to a glutamic acid residue led to a reduced affinity of a protein for its receptor due to structural level changes (page 2129; abstract). Moreover, Lazar, E., et. al. (Transforming growth factor alpha: mutation of aspartic acid 47 and leucine 48 results in different biological activities. Molecular and Cellular Biology, 8(3), 1247–1252; Published 1988, Published Online 03/31/2023) teaches that biological activity of a protein was maintained when an aspartic acid was mutated to an alanine or asparagine, but reduced when substituted with a serine or glutamic acid (page 1247, abstract). Lazar, E., et. al. goes on to teach conserved mutation of a leucine to alanine resulted in a complete loss of binding of a protein and mutation to isoleucine or methionine resulted in very low activities (page 1247, abstract). Furthermore, Ju, G., et. al. (Conversion of the interleukin 1 receptor antagonist into an agonist by site-specific mutagenesis. Immunology, 88(7), 2658-2662; Published 04/01/1991) teaches that a protein that had no agonist activity gained agonist activity after a mutation of a single amino acid from lysine to aspartic acid. Taken together, Burgess, W. H., et. al., Lazar, E., et. al., and Ju, G., et. al. teach that even a single substitution of an amino acid can change the biological property of a protein, including its structure and/or function.
In light of the Supreme Court decision In re Amgen Inc. et al. v. Sanofi et al., 143 S. Ct. 1243 (2023), hereafter Amgen, updated guidelines were provided regarding the assessment of enablement (Federal Register, pp. 1563–1566; Published 01/10/2024). In Amgen, the Supreme Court unanimously affirmed that a genus of monoclonal antibodies were not enabled because when a range within a genus is claimed, there must be reasonable enablement of the scope of the range. The Court found in Amgen that due to the large number of possible candidates within the scope of the claims and the specification's corresponding lack of structural guidance, it would have required undue experimentation to synthesize and screen each candidate to determine which compounds in the claimed class exhibited the claimed functionality. Collectively, the prior art and Court teach that it is unpredictable whether or not peptide variants will have similar structure and/or function, even when only one amino acid is mutated. It would thus require undue experimentation to screen the many variants
In the instantly claimed invention, there would be for each one. Moreover, it would require undue experimentation to determine the safety and efficacy of unconventional vaccination routes, including IP, oral, buccal, sublingual, and topical. There would also be undue experimentation to determine if the described epitopes contained within the immunogen of instant claims can elicit a neutralizing antibody.
For the reasons discussed above, undue experimentation would be required to practice the claimed invention commensurate with the scope of the claims, as discussed above. Reasonable correlation must exist between the scope of the claims and scope of enablement set forth. It would take undue trials and errors to practice the claimed invention in view of the quantity of experimentation necessary, the limited working examples, the unpredictability of the art, the lack of sufficient guidance in the specification, and the breadth of the claims.
Improper Markush Rejection
19. Claims 1 – 10 are rejected on the basis that they contain an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721–22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984).
The improper Markush grouping includes species of the claimed invention that do not share both a substantial structural feature and a common use that flows from the substantial structural feature. The members of the improper Markush grouping do not share a substantial structural feature and a common use that flows from the substantial structural feature for the following reasons:
MPEP 803.02 provides guidance on the analysis of a proper Markush group. Members of a proper Markush group are disclosed in the specification to possess at least one property in common which is mainly responsible for their function in the claimed relationship, and it is clear from their very nature or from the prior art that all of them possess this property. The MPEP further provides that in the members of a proper Markush group there should be (1) a common utility, and (2) a substantial structural feature essential to that utility.
The Markush grouping of claims 1 – 10 is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: All of the members of each group do not appear to share a common core sequence that is required for any shared function. In fact, most do not share a function at all as they cause immune responses against different Dengue virus serotypes. Thus, the groups are improper and the claims are rejected due to a lack of a common function and/or a common substantial structural feature that is essential to a common function.
Regarding claims 1 – 3, drawn to SEQ ID NOs: 4 – 9, the specification discloses that the nucleic acid sequence of SEQ ID NO: 4 encodes for the amino acid sequence of SEQ ID NO: 5 (page 4, paragraph 0012; page 9, paragraphs 0047 and 0048); SEQ ID NO: 6 encodes for SEQ ID NO: 7 (page 4, paragraph 0013; page 9, paragraphs 0049 and 0050); and SEQ ID NO: 8 encodes for SEQ ID NO: 9 (page 4, paragraph 0014; page 9, paragraphs 0051 and 0052), wherein SEQ ID NOs: 4 and 5; 6 and 7; and 8 and 9 are paired together (page 4, paragraph 0016). However, the amino acid sequences represented by SEQ ID NOs: 4, 6, and 8, and, thus, SEQ ID NOs: 5, 7, and 9, respectively, have no clearly shared or substantial structural feature among any with a shared function. SEQ ID NO: 7 is found within SEQ ID NO: 5, and, thus, there is 100% sequence similarity between SEQ ID NOs: 5 and 7 (see the percent identities as reproduced below on the left). However, there is not 100% sequence similarity between SEQ ID NOs: 5 and 9 or SEQ ID NOs: 7
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and 9, but rather 99.7% and 25.1% identity, respectively (see the percent identities as reproduced above on the right and below on the top left, correspondingly). Thus, SEQ ID NOs: 5, 7, and 9, corresponding to SEQ ID NOs: 4, 6, and 8, accordingly, are an improper Markush group. This rejection affects all dependent claims, i.e., claims 4 – 10, which are dependent on claim 1.
Regarding claim 2, drawn to SEQ ID NOs: 1 – 3, 5, 7, and 9, the specification discloses that the SEQ ID NO: 1 encodes for a vector comprising a mutated recombinant light chain of tetanus neurotoxin (DrTeNTLC; page 7, paragraph 0033); SEQ ID NO: 2 encodes for a vector comprising a recombinant heavy chain of tetanus neurotoxin (DrTeNTC; page 7, paragraph 0033); and SEQ ID NO: 3 encodes for a vector comprising a detoxified mutated recombinant full length tetanus neurotoxin (DrTeNTFL; page 7, paragraph 0033). The specification also discloses that SEQ ID NOs: 5, 7, or 9 are amino acid sequences embedded in or chemically attached to SEQ ID NOs: 1, 2, or 3, which are indefinite, as discussed above in paragraph 13. SEQ ID NOs: 5, 7, and 9 are an improper Markush group for reasons discussed in the previous paragraph. SEQ ID NO: 1 is found within SEQ ID NO: 3, and, thus, there is 100% sequence similarity between SEQ ID NOs: 1 and 3 (see the sequence identities reproduced below on the top right). However, there is not 100% sequence similarity between SEQ ID NOs: 1 and 2 and SEQ ID NOs: 2 and 3, but rather 21.3% and 92.9% similarity, respectively (see the percent identities as reproduced below on the bottom left and bottom right, accordingly). Thus, SEQ ID NOs: 1 – 3 are an improper Markush group.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single, substantial structural similarity as well as a common use. In light of the correspondence on 12/20/2025, applicant should either amend the claims to recite only the elected individual species or grouping of species that share a substantial structural feature as well as a common use, or present sufficient evidence that the species recited overcome this rejection.
This is a rejection on the merits and may be appealed to the Board of Patent Appeals and Interferences in accordance with 35 U.S.C. §134 and 37 CFR 41.31(a)(1).
Conclusion
21. Claims 1 – 10 are rejected. No claims are allowed.
22. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Hallie N. Pennington, Ph.D. whose telephone number is (571)272–6781. The examiner can normally be reached M–Th 7:30–5:30 ET.
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/Hallie N. Pennington, Ph.D./Examiner, Art Unit 1671
/Michael Allen/Supervisory Patent Examiner, Art Unit 1671