DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
1. Claims 1-26 as amended on March 07, 2023 are pending and under consideration.
Priority
2. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
It is noted that the examiner has established a priority date of January 29, 2021 for claims 1-26 of the instant application because the priority of the instantly claimed invention is based on the prior filed application KR10-2020-0113989 which is written in Korean. The prior filed application has not been translated and the Examiner is unable to determine the information in the document.
If applicant disagrees with any rejection set forth in this action based on examiner's establishment of a priority date of January 29, 2021 for claims 1-26, then applicant is invited to submit a proper translation of the priority document and to point to page and line where support can be found establishing an earlier priority date. If applicant choses to file a translation, then the translation must be filed together with a statement that the translation of the certified copy is accurate. See 35 U.S.C. 119 (b)(3), 37 C.F.R. 1.55(g)(3)(4), 37 C.F.R. 1.78(d)(7), and MPEP 1895.01.
Drawings
3. Figure 1 should be designated by a legend such as --Prior Art-- because only that which is old is illustrated. See MPEP § 608.02(g) and Lan et al. (Nature 14 May 2020 581: 215-220), Fig. 1C. Corrected drawings in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. The replacement sheet(s) should be labeled “Replacement Sheet” in the page header (as per 37 CFR 1.84(c)) so as not to obstruct any portion of the drawing figures. If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
4. The drawings are objected to because the RBD protein sequence in Figure 2 should be labeled as SEQ ID NO: 1. Additionally, the description of Figure 2 refers to red and blue aspects of the drawing, however color drawings have not been submitted.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
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.
5. Claims 1-26 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.
The term "having reduced binding affinity to an ACE2 receptor" in claim 1 is a relative term which renders claims 1-26 indefinite. The term "having reduced binding affinity to an ACE2 receptor" is not defined by the claims, 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. The specification does not teach at what point the binding affinity to an ACE2 receptor is considered to be reduced or to what the binding affinity of the coronavirus-derived receptor-binding domain variant is being compared to determine the reduction in affinity.
Section 2171 of the M.P.E.P. states
Two separate requirements are set forth in 35 U.S.C. 112(b) and pre-AIA 35 U.S.C. 112, second paragraph, namely that:
(A) the claims must set forth the subject matter that the inventor or a joint inventor regards as the invention; and
(B) the claims must particularly point out and distinctly define the metes and bounds of the subject matter to be protected by the patent grant.
The first requirement is a subjective one because it is dependent on what the inventor or a joint inventor for a patent regards as his or her invention. Note that although pre-AIA 35 U.S.C. 112, second paragraph, uses the phrase "which applicant regards as his invention," pre-AIA 37 CFR 1.41(a) provides that a patent is applied for in the name or names of the actual inventor or inventors.
The second requirement is an objective one because it is not dependent on the views of applicant or any particular individual, but is evaluated in the context of whether the claim is definite — i.e., whether the scope of the claim is clear to a hypothetical person possessing the ordinary level of skill in the pertinent art.
In the instant case of term "having reduced binding affinity to an ACE2 receptor", one of skill in the art could find representative examples in the art which have been defined in such terms, however, it is unclear at what point one of skill in the art would be infringing on the claims without limitations as to the metes and bounds of term "having reduced binding affinity to an ACE2 receptor" and without limitations to what the binding affinity of the coronavirus-derived receptor-binding domain variant is being compared to determine the reduction in affinity.
Claim 3 is drawn to “at least one mutation selected from the group consisting of: a mutation of amino acids L137 and F168; and a mutation of amino acid G184.” It is unclear if the Markush group includes only potential mutations of L137 and F168, with the G184 mutation being a mutation in addition to the Markush group, or if the Markush group includes L137, F168 and G184 as alternative potential mutations. The claim will be interpreted to include L137, F168 and G184 as alternative potential mutations.
Claim 5 is drawn to “at least one substitution selected from the group consisting of: a substitution of amino acids L137A and F168A; and a substitution of amino acid G184D.” It is unclear if the Markush group includes only potential substitutions of L137A and F168A, with the G184D substitution being a substitution in addition to the Markush group, or if the Markush group includes L137A, F168A and G184D as alternative potential substitutions. The claim will be interpreted to include L137A, F168A and G184D as alternative potential substitutions.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
6. Claims 1-26 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 claim are broadly drawn to a coronavirus-derived receptor-binding domain variant having reduced binding affinity to an ACE2 receptor. The claims encompass any receptor-binding domain variant from any coronavirus having reduced binding affinity to any ACE2 receptor.
Coronavirus encompasses a large family of viruses. Coronaviridae Study Group of the International Committee on Taxonomy of Viruses (Nat Microbiol 5, 536–544 (2020). https://doi.org/10.1038/s41564-020-0695-z) teaches that there are 39 species of coronavirus in 27 subgenera with 10 new species pending, making a total of 49 species of coronavirus . See paragraph bridging pp. 537-538, Box 4, and Figs. 1 and 2. Thus, the receptor-binding domain variants are derived from a large genus of coronavirus.
The ACE2 receptor also encompasses a large family of orthologs and isoforms from any species. The ACE2 proteins vary significantly in sequence identity. NCBI Blast (ref NP_001358344.1, angiotensin-converting enzyme 2 isoform 1 precursor Blast, downloaded Nov. 14, 2025, https://blast.ncbi.nlm.nih.gov/Blast.cgi#NP_001094923). Thus, the large genus receptor-binding domain variants encompass variants having reduced binding to a large genus of ACE2 receptors.
Differences in the receptor-binding domain between coronavirus species can affect the binding receptor-binding domain to ACE2. In particular, US 2023/0346916 A1 (Du et al. Nov. 2, 2023) teaches the receptor-binding domains (RBDs) of SARS-CoV-2, SARS-CoV, and MERS-CoV vary in sequence identity, but share conserved residues. See ¶ 0025 and Fig. 1. Du teaches that there were significant differences between binding of SARS-CoV-2 RBD and SARS-CoV RBD to cell-associated human (hACE2) or bat (bACE2) ACE2 receptor. The MERS-CoV RBD exhibited no binding to cell-associated hACE2 or bACE2 receptor. See ¶¶ 0027 and 0097 and Fig. 3C. Thus, differences in structure of the RBDs and ACE receptor can significantly and unpredictably affect the binding of the RBDs to an ACE2 receptor Thus, given the above, it is clear that in the protein biochemistry arts an adequate written description is essential for one of skill in the art to make and use the claimed invention.
Although drawn to DNA arts, the findings in University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc. are relevant to the instant claims. The Federal Circuit addressed the application of the written description requirement to DNA-related inventions in University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997). The court stated that "[a] written description of an invention involving a chemical genus, like a description of a chemical species, requires a precise definition, such as by structure, formula, [or] chemical name,' of the claimed subject matter sufficient to distinguish it from other materials." Id. At 1567, 43 USPQ2d at 1405. The court also stated that
a generic statement such as "vertebrate insulin cDNA" or "mammalian insulin cDNA" without more, is not an adequate written description of the genus because it does not distinguish the genus from others, except by function. It does not specifically define any of the genes that fall within its definition. It does not define any structural features commonly possessed by members of the genus that distinguish them from others. One skilled in the art therefore cannot, as one can do with a fully described genus, visualize or recognize the identity of the members of the genus. A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is.
Id. At 1568, 43 USPQ2d at 1406. The court concluded that "naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material." Id.
Finally, the court addressed the manner by which a genus of cDNAs might be described. "A description of a genus of cDNAs may be achieved by means of a recitation of a representative number of cDNAs, defined by nucleotide sequence, falling within the scope of the genus or of a recitation of structural features common to the members of the genus, which features constitute a substantial portion of the genus." Id.
The Federal Circuit has recently clarified that a DNA molecule can be adequately described without disclosing its complete structure. See Enzo Biochem, Inc. V. Gen-Probe Inc., 296 F.3d 1316, 63 USPQ2d 1609 (Fed. Cir. 2002). The Enzo court adopted the standard that "the written description requirement can be met by 'show[ing] that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics ... 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. " Id. At 1324, 63 USPQ2d at 1613 (emphasis omitted, bracketed material in original).
The inventions at issue in Lilly and Enzo were DNA constructs per se, the holdings of those cases are also applicable to claims such as those at issue here.
Thus, the instant specification may provide an adequate written description of a coronavirus-derived receptor-binding domain variant having reduced binding affinity to an ACE2 receptor, per Lilly by structurally describing a representative number of said receptor-binding domain variants, or by describing "structural features common to the members of the genus, which features constitute a substantial portion of the genus." Alternatively, per Enzo, the specification can show that the claimed invention is complete "by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics."
In this case, the specification does not provide an adequate written description of a coronavirus-derived receptor-binding domain variant having reduced binding affinity to an ACE2 receptor in a manner that satisfies either the Lilly or Enzo standards.. The specification discloses an RBD variant (RBDm (L137A, F168A)) exhibited low binding affinity the human ACE2 receptor and the RBD variant G184D did not bind to ACE2 at all. See pp. 83-84-Example 2, Fig. 26 and Table 5. Additionally, the specification teaches that in the case where further amino acid substitutions (G164A, V165A, F168A, Q175A, S176A, N183A) were present, in addition to L137A and F168A, the binding affinity was decreased, but in the case where L137A and F168A were not present (G164A, V165A, F168A, Q175A, S176A and N183A variants), binding affinity was maintained. See p. 85-1st paragraph. This does not provide a description of a coronavirus-derived receptor-binding domain variant having reduced binding affinity to an ACE2 receptor that would satisfy the standard set out in Enzo because the specification only discloses a few substitution mutations in a single type of RBD from SARS-CoV-2 that can affect its binding to human ACE2. However, the claims encompass any receptor-binding domain variant from any coronavirus having reduced binding affinity to any ACE2 receptor as set forth above and the disclosed substitution would not predictably affect the binding affinity of any RBD to any ACE2 receptor in the same manner. Thus, the few disclosed substitution mutations in a single type of RBD from SARS-CoV-2 do not provide an adequate description of the claimed invention.
The specification also fails to describe a coronavirus-derived receptor-binding domain variant having reduced binding affinity to an ACE2 receptor by the test set out in Lilly. The specification describes only a few substitution mutations in a single type of RBD from SARS-CoV-2 and their affect on binding to human ACE2 receptor. Therefore, the necessarily fails to describe a "representative number" of species of a coronavirus-derived receptor-binding domain variant having reduced binding affinity to an ACE2 receptor because the claims encompass any receptor-binding domain variant from any coronavirus having reduced binding affinity to any ACE2 receptor and the disclosed substitution would not predictably affect the binding affinity of any RBD to any ACE2 receptor in the same manner In addition, the specification also does not describe "structural features common to the members of the genus, which features constitute a substantial portion of the genus."
Thus, for the reasons set forth above the specification does not provide an adequate written description of a coronavirus-derived receptor-binding domain variant having reduced binding affinity to an ACE2 receptor that is required to practice the claimed invention or reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the broadly claimed invention.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
7. Claims 1-4, 6-8, 17, 21, 22, 24 and 26 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e. a natural product) without significantly more. The claim(s) recite(s) a coronavirus-derived receptor-binding domain (RBD) variant having reduced binding affinity to an ACE2 receptor, which encompasses natural coronavirus RBD variants. This judicial exception is not integrated into a practical application because the recitation of a vaccine or pharmaceutical composition are only suggestive of an intended use that does not change the structure of the RBD variant. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the recitation of a fusion protein of the RBD variant encompasses the natural coronavirus spike protein which is a fusion protein and the coronavirus contains nucleic acids which express the spike protein in infected host cells.
The Mayo framework provides that first whether the claims at issue are directed to a patent-ineligible concept is determined. If the answer is yes, then the elements of each claim both individually and “as an ordered combination” are considered to determine whether additional elements “transform the nature of the claim” into a patent-eligible application. The second step—known as the “inventive concept”—requires that claims include elements which would render the method both new and useful.
The recent Eligibility Guidance (2014 Interim Guidance on Patent Subject Matter Eligibility (Interim Eligibility Guidance and 2018 Revised Patent Subject Matter Eligibility Guidance published in the Federal Register (84 FR 50) on January 7, 2019) address the subject matter eligibility analysis for all claims (i.e., machine, composition of matter, manufacture and process claims). The analysis is to be used for evaluating whether a claim is drawn to patent-eligible subject matter.
Step 1 determines whether the claim is directed to a process, machine, manufacture, or composition of matter. If the claim is directed to a statutory category, proceed to Step 2.
Step 2 is the two-part analysis for claims directed to laws of nature, natural phenomena, and abstract ideas (the judicially recognized exceptions).
In Step 2A, determine whether the claim is directed to a law of nature, a natural phenomenon, or an abstract idea (judicial exceptions). “Directed to” means the exception is recited in the claim, i.e., the claim sets forth or describes the exception.
In Prong One of Step 2A it is determined if the claim recites a judicial exception. If the claim recites a judicial exception then Prong Two of Step 2A determines whether the claims recites additional elements that integrate the exception into a practical application.
If the answer to Prong Two of Step 2A is no, Step 2B is used to determine whether the claim as a whole amounts to significantly more than the exception by the recitation of additional elements.
The present claims are directed to a product so Step 1 is satisfied.
With respect to Step 2A MPEP 2106.04(c) II(C)(2) teaches:
In Myriad, the Supreme Court made clear that not all changes in characteristics will rise to the level of a marked difference, e.g., the incidental changes resulting from isolation of a gene sequence are not enough to make the isolated gene markedly different. Myriad, 569 U.S. at 580, 106 USPQ2d at 1974-75. The patentee in Myriad had discovered the location of the BRCA1 and BRCA2 genes in the human genome, and isolated them, i.e., separated those specific genes from the rest of the chromosome on which they exist in nature. As a result of their isolation, the isolated genes had a different structural characteristic than the natural genes, i.e., the natural genes had covalent bonds on their ends that connected them to the rest of the chromosome, but the isolated genes lacked these bonds. However, the claimed genes were otherwise structurally identical to the natural genes, e.g., they had the same genetic structure and nucleotide sequence as the BRCA genes in nature. The Supreme Court concluded that these isolated but otherwise unchanged genes were not eligible, because they were not different enough from what exists in nature to avoid improperly tying up the future use and study of the naturally occurring BRCA genes. See, e.g., Myriad, 569 U.S. at 585, 106 USPQ2d at 1977 ("Myriad's patents would, if valid, give it the exclusive right to isolate an individual’s BRCA1 and BRCA2 genes … But isolation is necessary to conduct genetic testing") and 569 U.S. at 593, 106 USPQ2d at 1980 (describing how would-be infringers could not avoid the scope of Myriad’s claims). In sum, the claimed genes were different, but not markedly different, from their naturally occurring counterparts (the BRCA genes), and thus were product of nature exceptions.
In Ambry Genetics, the court identified claimed DNA fragments known as "primers" as products of nature, because they lacked markedly different characteristics. University of Utah Research Foundation v. Ambry Genetics Corp., 774 F.3d 755, 113 USPQ2d 1241 (Fed. Cir. 2014). The claimed primers were single-stranded pieces of DNA, each of which corresponded to a naturally occurring double-stranded DNA sequence in or near the BRCA genes. The patentee argued that these primers had markedly different structural characteristics from the natural DNA, because the primers were synthetically created and because "single-stranded DNA cannot be found in the human body". The court disagreed, concluding that the primers’ structural characteristics were not markedly different than the corresponding strands of DNA in nature, because the primers and their counterparts had the same genetic structure and nucleotide sequence. 774 F.3d at 760, 113 USPQ2d at 1243-44. The patentee also argued that the primers had a different function than when they are part of the DNA strand because when isolated as a primer, a primer can be used as a starting material for a DNA polymerization process. The court disagreed, because this ability to serve as a starting material is innate to DNA itself, and was not created or altered by the patentee:
In fact, the naturally occurring genetic sequences at issue here do not perform a significantly new function. Rather, the naturally occurring material is used to form the first step in a chain reaction--a function that is performed because the primer maintains the exact same nucleotide sequence as the relevant portion of the naturally occurring sequence. One of the primary functions of DNA’s structure in nature is that complementary nucleotide sequences bind to each other. It is this same function that is exploited here--the primer binds to its complementary nucleotide sequence. Thus, just as in nature, primers utilize the innate ability of DNA to bind to itself.
Ambry Genetics, 774 F.3d at 760-61, 113 USPQ2d at 1244. In sum, because the characteristics of the claimed primers were innate to naturally occurring DNA, they lacked markedly different characteristics from nature and were thus product of nature exceptions. A similar result was reached in Marden, where the court held a claim to ductile vanadium ineligible, because the "ductility or malleability of vanadium is . . . one of its inherent characteristics and not a characteristic given to it by virtue of a new combination with other materials or which characteristic is brought about by some chemical reaction or agency which changes its inherent characteristics". In re Marden, 47 F.2d 958, 959, 18 CCPA 1057, 1060, 8 USPQ 347, 349 (CCPA 1931
For Prong One of Step 2A the claims recite a judicial exception, i.e. a natural product which is a natural phenomenon. In particular, the claims recite a coronavirus-RBD variant with reduced binding affinity to an ACE2 receptor, which encompasses natural coronavirus spike protein RBD variants. In particular, US 2023/0346916 A1 (Du et al. Nov. 2, 2023) teaches natural SARS-CoV-2 variants containing V483A and F486L mutations, which correspond to the claimed V165A and F168 mutations. See ¶ [0042] and Fig. 17. Mugnai et al. (bioRxiv Dec., 1 2020, 11.30.405340; doi: https://doi.org/10.1101/2020.11.30.405340, pp. 1-27 and Supporting Information), teaches that a F486L mutation in the RBD , which corresponds to F186 as claimed, reduces the affinity of the RBD for ACE2. See p. 11-1st full paragraph and Table 1. So the answer to Prong One of Step 2A is yes the claims do recite a judicial exception.
For Prong Two of Step 2A the claims do not integrate the exception into a practical application. The judicial exception is not integrated into a practical application because the additional limitations of a vaccine or pharmaceutical composition for preventing or treating coronavirus infection are only suggestive of an intended use that does not change the structure of the RBD variant. So the answer to Prong Two of Step 2A is no.
With respect to Step 2B MPEP 2106.05 (I) teaches that
The second part of the Alice/Mayo test is often referred to as a search for an inventive concept. Alice Corp. Pty. Ltd. v. CLS Bank Int'l, 573 U.S. 208, 217, 110 USPQ2d 1976, 1981 (2014) (citing Mayo Collaborative Servs. v. Prometheus Labs., Inc., 566 U.S. 66, 71-72, 101 USPQ2d 1961, 1966 (2012)).
An inventive concept "cannot be furnished by the unpatentable law of nature (or natural phenomenon or abstract idea) itself." Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016). See also Alice Corp., 573 U.S. at 21-18, 110 USPQ2d at 1981 (citing Mayo, 566 U.S. at 78, 101 USPQ2d at 1968 (after determining that a claim is directed to a judicial exception, "we then ask, ‘[w]hat else is there in the claims before us?") (emphasis added)); RecogniCorp, LLC v. Nintendo Co., 855 F.3d 1322, 1327, 122 USPQ2d 1377 (Fed. Cir. 2017) ("Adding one abstract idea (math) to another abstract idea (encoding and decoding) does not render the claim non-abstract"). Instead, an "inventive concept" is furnished by an element or combination of elements that is recited in the claim in addition to (beyond) the judicial exception, and is sufficient to ensure that the claim as a whole amounts to significantly more than the judicial exception itself. Alice Corp., 573 U.S. at 27-18, 110 USPQ2d at 1981 (citing Mayo, 566 U.S. at 72-73, 101 USPQ2d at 1966).
With respect to Step 2B MPEP 2106.05 (d) teaches that:
Another consideration when determining whether a claim recites significantly more than a judicial exception is whether the additional element(s) are well-understood, routine, conventional activities previously known to the industry.
If the additional element (or combination of elements) is a specific limitation other than what is well-understood, routine and conventional in the field, for instance because it is an unconventional step that confines the claim to a particular useful application of the judicial exception, then this consideration favors eligibility. If, however, the additional element (or combination of elements) is no more than well-understood, routine, conventional activities previously known to the industry, which is recited at a high level of generality, then this consideration does not favor eligibility.
. . .
On the other hand, Mayo Collaborative Servs. v. Prometheus Labs., Inc., 566 U.S. 66, 67, 101 USPQ2d 1961, 1964 (2010) provides an example of additional elements that were not an inventive concept because they were merely well-understood, routine, conventional activity previously known to the industry, which were not by themselves sufficient to transform a judicial exception into a patent eligible invention. Mayo Collaborative Servs. v. Prometheus Labs., Inc., 566 U.S. 66, 79-80, 101 USPQ2d 1969 (2012) (citing Parker v. Flook, 437 U.S. 584, 590, 198 USPQ 193, 199 (1978) (the additional elements were "well known" and, thus, did not amount to a patentable application of the mathematical formula)). In Mayo, the claims at issue recited naturally occurring correlations (the relationships between the concentration in the blood of certain thiopurine metabolites and the likelihood that a drug dosage will be ineffective or induce harmful side effects) along with additional elements including telling a doctor to measure thiopurine metabolite levels in the blood using any known process. 566 U.S. at 77-79, 101 USPQ2d at 1967-68. The Court found this additional step of measuring metabolite levels to be well-understood, routine, conventional activity already engaged in by the scientific community because scientists "routinely measured metabolites as part of their investigations into the relationships between metabolite levels and efficacy and toxicity of thiopurine compounds." 566 U.S. at 79, 101 USPQ2d at 1968. Even when considered in combination with the other additional elements, the step of measuring metabolite levels did not amount to an inventive concept, and thus the claims in Mayo were not eligible. 566 U.S. at 79-80, 101 USPQ2d at 1968-69.
Additionally MPEP 2106.05 (d) II teaches that:
The courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity.
i. Determining the level of a biomarker in blood by any means, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017);
ii. Using polymerase chain reaction to amplify and detect DNA, Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1377, 115 USPQ2d 1152, 1157 (Fed. Cir. 2015);
iii. Detecting DNA or enzymes in a sample, Sequenom, 788 F.3d at 1377-78, 115 USPQ2d at 1157); Cleveland Clinic Foundation 859 F.3d at 1362, 123 USPQ2d at 1088 (Fed. Cir. 2017);
iv. Immunizing a patient against a disease, Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057, 1063, 100 USPQ2d 1492, 1497 (Fed. Cir. 2011);
v. Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546;
vi. Freezing and thawing cells, Rapid Litig. Mgmt. 827 F.3d at 1051, 119 USPQ2d at 1375;
vii. Amplifying and sequencing nucleic acid sequences, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014); and
viii. Hybridizing a gene probe, Ambry Genetics, 774 F.3d at 764, 113 USPQ2d at 1247.
The additional limitations of a fusion protein of the RBD variant does not amount to significantly more because the fusion proteins encompasses the natural coronavirus spike protein which is a fusion protein. In particular, US 2023/0234992 A1 (Biancucci et al. July 27, 2023, effectively filed June 5, 2020), teaches the spike (S) protein is a homotrimeric class I fusion protein with two subunits in each spike monomer (or “protomer”), called “S1” and “S2”, which are responsible for receptor recognition and membrane fusion, respectively. See ¶ 0362. The additional limitations of a nucleic and host cells encoding the RBD variant does not amount to significantly more because a coronavirus contains nucleic acids which express the spike protein in infected host cells. See US 2023/0346916 A1 (Du et al. Nov. 2, 2023), ¶¶ 0003-0005. Thus the claimed RBD variant and the nucleic and host cells encoding it do not have a significanly different structure or function from the naturally occuring RBD variant and the nucleic and host cells encoding it. The absence of structural differences taken together with the lack of any functional difference between the claimed protein and cells and their natural counterparts demonstrates that the recited products are not markedly different from what exists in nature.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
8. Claim(s) 1-8 and 17-26 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by US 2023/0234992 A1 (Biancucci et al. July 27, 2023, effectively filed June 5, 2020), “Biancucci”.
Biancucci teaches modified beta coronavirus antigens, specifically modified Spike (S) proteins or S protein fragments, that include one or more substitution mutations designed to increase stability or decrease the risk of antibody dependent enhancement; features desirable of a candidate beta coronavirus vaccine antigen. See abstract and ¶¶ 0006-0010.
Biancucci teaches SARS-CoV-2 spike protein binding domain substitutions predicted to knockout ACE2 binding. See Example 2 and Table 6.
Biancucci teaches multiple receptor binding domain (RBD) constructs for potentially reducing binding to ACE2. See Example 5 and Table 13.
Biancucci teaches several substitutions of L455 in the RBD, which corresponds to L137 as claimed, including L455A/L137A. See Example 5 and Table 13.
Biancucci teaches several substitutions of F486 in the RBD, which corresponds to F168 as claimed. See Example 5 and Table 13.
Biancucci teaches several mutants with substitutions of F486 in the RBD, F486T, H, N, or M, and the L455N substitution have reduced binding to ACE2. See Example 5, [0544] and Table 13.
Although Biancucci does not teach that the L455A/L137A RBD mutant has reduced binding to an ACE2 receptor, the structure of RBD mutant is the same as that claimed and thus it would have the same function.
Biancucci teaches the spike (S) protein is a homotrimeric class I fusion protein with two subunits in each spike monomer (or “protomer”), called “S1” and “S2”, which are responsible for receptor recognition and membrane fusion, respectively. See ¶ 0362.
SEQ ID NO: 90 of Biancucci comprising the F486T/F168T mutation comprises the S1 and S2 subunits of the spike protein. See Appendix and Chain A, Spike Glycoprotein (PDB: 7T3M_A 24-Aug-2022). Thus the RBD mutants are fused to a coronavirus derived substance.
Biancucci teaches vaccine compositions with the spike protein mutans include adjuvants including CPG dinucleotides (ODN) and aluminum salts. See ¶¶ 0383-393 and 0402.
Biancucci teaches vaccinating subjects with the spike protein mutants. See ¶¶ 0005, 0352, 0362, 0365, 0366, and 0480-0485.
Biancucci teaches using pharmaceutical grade compositions suitable for pharmaceutical use. See ¶¶ 0322, 0334, 0344, and 0345.
Biancucci teaches treating a subject with COVID-19 with the spike protein mutants. . See ¶¶ 0347, 0351, 0352, and 0425.
Biancucci teaches nucleic acid expression vectors and host cells for expressing the spike protein mutants. See ¶¶ 0408-0419.
9. Claim(s) 1-4, 6, 17, 21, and 22 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Mugnai et al. (bioRxiv Dec., 1 2020, 11.30.405340; doi: https://doi.org/10.1101/2020.11.30.405340, pp. 1-27 and Supporting Information), “Mugnai”.
Mugnai teaches that a G502P mutation, which corresponds to G184 as claimed, in the SARS-CoV-2 RBD diminished binding to the ACE2 protein. See abstract and p. 13-1st paragraph, p. 17-2nd paragraph, Table 1 and Figure S9.
Mugnai teaches that a G502D mutation in the SARS-CoV-2 RBD , which corresponds to G184D as claimed, reduces the avidity of the RBD for ACE2. See p. 17-2nd paragraph and Figure S9.
Mugnai teaches that a F486L mutation in the RBD , which corresponds to F186 as claimed, reduces the affinity of the RBD for ACE2. See p. 11-1st full paragraph and Table 1.
Regarding claims 17, 21 and 22, it is noted that the intended uses of the RBD variant as a vaccine or a pharmaceutical composition for preventing or treating coronavirus infection are not given weight for comparison of the claims with the prior art because a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art, which the limitations of claims 17, 21 and 22 do not.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
10. Claim(s) 1-26 are rejected under 35 U.S.C. 103 as being unpatentable over US 2023/0234992 A1 (Biancucci et al. July 27, 2023, effectively filed June 5, 2020), “Biancucci” as applied to claims 1-8 and 17-26 above in further view of US 2024/0270795 A1 (Nascimento et al. Aug. 15, 2024 effectively filed Aug. 17, 2020), “Nascimento”.
Biancucci teaches as set forth above
Biancucci also teaches that the SARS-βCoV spike protein RBD from SEQ ID NOs: 5-114 can be linked to IgG1 Fc. See ¶¶ 0337 and 0444.
Biancucci also teaches SARS-βCoV spike protein RBD-Fc fusion can elicit an immune response. See ¶ 0444.
Biancucci also teaches that the spike protein mutants can comprise a transmembrane domain (M protein) for membrane insertion. See ¶¶ 0057, 0059, 0361, and 0368.
Biancucci also teaches the spike protein mutants can be a dimer. ¶¶ 0474 and 0537.
Biancucci also teaches using glycine-serine linkers to link protein domains. See ¶¶ 0339, 0364 and 0445 and SEQ ID NO: 121
Biancucci teaches as set forth above, but does not teach making examples of the fusion proteins of claims 9-15 or the G184D substitution.
Nascimento teaches making fusion proteins of the SARS-COV-2 RBD. See abstract. ¶¶ 00137 and 0017.
Nascimento teaches the concerns of lower assay sensitivity for detecting SARS-COV-2 IgGs due to the small size of the RBD protein may be overcome by the molecular fusion of RBD and N (nucleocapsid) proteins. See ¶¶ 0004 and 0007.
Nascimento teaches N protein fusions with the SARS-COV-2 RBD. See ¶¶ 0009, 0010 and 0078.
Nascimento teaches IgG-Fc fusions with the SARS-COV-2 RBD with dimerization domains. See ¶¶ 0010, 0016, 0059 and 0071.
Nascimento teaches using glycine serine linkers. See ¶¶ 0059 and 0072.
Nascimento teaches the SARS-COV-2 RBD is linked to the N-terminus of the Fc domain. See SEQ ID NOs: 9, 10 and 43 and Appendix.
Nascimento teaches using the fusion proteins for improved detection of SARS-COV-2 and vaccines. See ¶¶ 0009-0012.
Nascimento teaches RBD fusion proteins can form dimers. See Example 1 and ¶ 0104.
Nascimento teaches a G502D substitution, which corresponds to G184D, increases expression of the RBD. See ¶¶ 0076 and 0079.
Although Nascimento does not teach that the G502D / G184D RBD mutant has reduced binding to an ACE2 receptor, the structure of RBD mutant is the same as that claimed and thus it would have the same function.
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of Biancucci and Nascimento and make fusion proteins with the spike RBD mutant proteins of Biancucci because Biancucci teaches the RBD can be linked to linked to IgG1 Fc with linkers, Nascimento teaches IgG-Fc fusions and N protein fusions with the RBD, and Nascimento teaches using the fusion proteins for improved detection of SARS-COV-2 and vaccines. One would have been motivated to make fusion proteins with the spike RBD mutant proteins to improve the function and impart new activities for detection and purification of the spike RBD mutant proteins and for use in detection of SARS-COV-2 and vaccines. One of skill in the art would have been motivated to modify the order of the linked fusion protein components to optimize the activity of the RBD fusion proteins.
Additionally, one of skill in the art would have been motivated to add a G502D substitution, which corresponds to G184D, to the spike RBD mutant proteins because Nascimento teaches a G502D substitution increases expression of the RBD, which would increase the amount of the RBD mutant proteins produced when the proteins are made.
Conclusion
11. No claims allowed.
12. Any inquiry concerning this communication or earlier communications from the examiner should be directed to PETER J REDDIG whose telephone number is (571)272-9031. The examiner can normally be reached M-F 8:30-5:30 Eastern Time.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Janet L Epps-Smith can be reached at 571-272-0757. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/PETER J REDDIG/Primary Examiner, Art Unit 1646
APPENDIX
Alignment of Bianucci SEQ ID NO: 90 with Spike glycoprotein
Query: Bianucci 90 Query ID: lcl|Query_7606136 Length: 1121
>Chain A, Spike glycoprotein [Severe acute respiratory syndrome coronavirus 2]
Sequence ID: 7ZSS_A Length: 1146
Range 1: 27 to 1146
Score:2315 bits(6000), Expect:0.0,
Method:Compositional matrix adjust.,
Identities:1119/1120(99%), Positives:1119/1120(99%), Gaps:0/1120(0%)
Query 1 AYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPF 60
AYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPF
Sbjct 27 AYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPF 86
Query 61 NDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYH 120
NDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYH
Sbjct 87 NDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYH 146
Query 121 KNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSK 180
KNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSK
Sbjct 147 KNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSK 206
Query 181 HTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYY 240
HTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYY
Sbjct 207 HTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYY 266
Query 241 VGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESI 300
VGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESI
Sbjct 267 VGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESI 326
Query 301 VRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTK 360
VRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTK
Sbjct 327 VRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTK 386
Query 361 LNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVG 420
LNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVG
Sbjct 387 LNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVG 446
Query 421 GNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGTNCYFPLQSYGFQPTNGVGYQ 480
GNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEG NCYFPLQSYGFQPTNGVGYQ
Sbjct 447 GNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQ 506
Query 481 PYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQQFG 540
PYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQQFG
Sbjct 507 PYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQQFG 566
Query 541 RDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQGVNCTEVPVAIHA 600
RDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQGVNCTEVPVAIHA
Sbjct 567 RDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQGVNCTEVPVAIHA 626
Query 601 DQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICASYQTQTNSPGSASS 660
DQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICASYQTQTNSPGSASS
Sbjct 627 DQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICASYQTQTNSPGSASS 686
Query 6