Notice of AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Disposition of Claims
Claims 1-4 are pending.
Examiner' s Note
All paragraph numbers (¶) throughout this office action, unless otherwise noted, are from the US PGPub of this application US20240374704A1, Published 11/14/2024.
Applicant is encouraged to utilize the new web-based Automated Interview Request (AIR) tool for submitting interview requests; more information can be found at https://www.uspto.gov/patent/laws-and-regulations/interview-practice.
Optional Authorization to Initiate Electronic Communications
The Applicant' s representative may wish to consider supplying a written authorization in response to this Office action to correspond with the Examiner via electronic mail (e-mail). This authorization is optional on the part of the Applicant' s representative, but it should be noted that the Examiner may not initiate nor respond to communications via electronic mail unless and until Applicant' s representative authorizes such communications in writing within the official record of the patent application. A sample authorization is available at MPEP § 502.03, part II. If Applicant' s representative chooses to provide this authorization, please ensure to include a valid e-mail address along with said authorization.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 11/05/2024 and 05/30/2025 are is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Specification
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The abstract of the disclosure is objected to because of the use of legal phraseology (e.g. the use of “e.g.” or “exempli gratia” should be replaced with “for example” or deleted from the abstract.) A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Drawings
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).
The drawings are objected to because of the reference to color in the drawings (e.g. Figs. 11-13.) 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.
Claim Objections
Claim 1 is objected to because of the following informalities: the definition of the abbreviations “S protein”, “M protein”, and “E protein” are not provided. For clarity, it is requested that the first recitation of an abbreviation within a claim set be preceded by its full-length name (i.e. … spike (S) protein, membrane (M) protein, envelope (E) protein...).
Appropriate correction is required.
Claim Interpretation
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
Claim 1 is drawn to an ungulate-derived polyclonal human immunoglobulin composition, comprising a population of human immunoglobulins,
wherein the population of human immunoglobulins specifically binds a coronavirus protein selected from coronavirus spike (S) protein, coronavirus membrane (M) protein, coronavirus envelope € protein, or coronavirus Nucleocapsid (N) protein, or a combination thereof.
Claim 2 is drawn to a polyclonal human immunoglobulin composition, produced by immunizing a transgenic ungulate with a coronavirus protein or an antigenic fragment thereof, wherein the composition comprises a population of human immunoglobulins.
Claim 3 is drawn to a polyclonal human immunoglobulin composition, comprising a population of human immunoglobulins,
wherein the population of human immunoglobulins specifically binds a coronavirus protein selected from coronavirus S protein, coronavirus M protein, coronavirus E protein, or coronavirus Nucleocapsid protein, or a combination thereof,
wherein the population of human immunoglobulins comprise glycans covalently linked to the human immunoglobulins, and
wherein the glycans comprise at least about 70%, at least about 80%, or at least about 90% N-Glycolylneuraminic acid (NGNA)-bearing glycans.
Claim 4 is drawn to a method of making polyclonal human immunoglobulin for treatment of coronavirus disease, comprising administering an antigen comprising a coronavirus protein selected from coronavirus S protein, coronavirus M protein, coronavirus E protein, or coronavirus Nucleocapsid protein or an antigenic fragment thereof, or a polynucleotide encoding the antigen, to a transgenic ungulate, wherein the transgenic ungulate comprises a genome comprising a human immunoglobulin locus or an artificial chromosome comprising a human immunoglobulin locus, wherein the transgenic ungulate produces a population of human immunoglobulins that specifically binds the coronavirus protein selected from coronavirus S protein, coronavirus M protein, coronavirus E protein, or coronavirus Nucleocapsid protein, or a combination thereof.
Claim Rejections - 35 USC § 112(b); Second Paragraph
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1 and 3-4 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.
Claim 1 recites an ungulate-derived polyclonal human immunoglobulin composition, comprising a population of human immunoglobulins,
wherein the population of human immunoglobulins specifically binds a coronavirus protein selected from coronavirus S protein, coronavirus M protein, coronavirus E protein, or coronavirus Nucleocapsid protein, or a combination thereof.
Claim 3 recites a polyclonal human immunoglobulin composition, comprising a population of human immunoglobulins, wherein the population of human immunoglobulins “specifically binds a coronavirus protein selected from coronavirus S protein, coronavirus M protein, coronavirus E protein, or coronavirus Nucleocapsid protein, or a combination thereof…”.
Claim 4 recites a similar limitation as claims 1 and 3.
The phrase “specifically binds a coronavirus protein selected from coronavirus S protein, coronavirus M protein, coronavirus E protein, or coronavirus Nucleocapsid protein, or a combination thereof” does not clearly identify the antigen required to be “specifically bound”. A “coronavirus S protein” is not a singular defined protein, nor is a “coronavirus M protein”, “coronavirus E protein”, or a “coronavirus nucleocapsid protein”. Each term encompasses a class of proteins from different coronaviruses, species, strains, and variants. Therefore, it is unclear whether the claimed population of human immunoglobulins must “specifically bind” one selected coronavirus protein, all proteins within a selected coronavirus protein class, or some undefined subset of proteins within the selected class.
The specification defines “specifically binds” in relative terms. At ¶[0097], it states that an immunoglobulin specifically binds a target if it binds with greater affinity, avidity, more readily, and/or with greater duration than it binds to alternative proteins or substances. The same paragraph further states that specific binding does not require exclusive binding. However, the specification does not identify a required assay, binding threshold, comparator antigen, coronavirus species, coronavirus strain, protein sequence, or portion of the polyclonal immunoglobulin population that must bind to the antigen.
As a result, one skilled in the art cannot determine, with reasonable certainty, whether a polyclonal human immunoglobulin composition falls within the scope of claims 1, 3, and 4. For example, it is unclear whether a composition that specifically binds SARS-CoV-2 spike protein, but does not specifically bind another coronavirus spike protein, satisfies the claim. It is also unclear what binding comparison must be used to determine whether the population specifically binds “coronavirus S protein” rather than another coronavirus protein or another unrelated protein.
Accordingly, the metes and bounds of claims 1, 3, and 4 are unclear.
Claim 3 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 3 recites that the population of human immunoglobulins comprises glycans and that “the glycans comprise at least about 70%, at least about 80%, or at least about 90% N-glycolylneuraminic acid (NGNA)-bearing glycans.” It is unclear how the percentage of NGNA-bearing glycans is to be determined. The claim does not specify whether the recited percentage is measured relative to all glycans in the composition, all N-linked glycans, all sialylated glycans, all terminal sialic acid residues, or antibody molecules bearing at least one NGNA-containing glycan. The claim also does not specify whether the percentage is determined for the entire polyclonal immunoglobulin population, an IgG-enriched fraction, a particular antibody species within the population, or another defined sample.
The specification does not resolve this ambiguity. The specification reports glycan data using different analytical contexts. Table 6 reports 13.8% “N-glycolyneuraminic (NG)-cont. Structures” by mass spectrometry (¶[0197]). Table 7 separately reports “0.90” NGNA content for human IgG from sample #468 in a sialic-acid analysis, and ¶[0198] states that TcB-produced human IgG contains “>90% NGNA.” The claim does not identify which analytical approach, denominator, or sample type controls the claimed “at least about 70%, at least about 80%, or at least about 90% NGNA-bearing glycans” limitation.
As a result, one skilled in the art cannot determine with reasonable certainty whether a polyclonal human immunoglobulin composition satisfies claim 3. A composition could appear to meet the claim if NGNA is calculated as a percentage of sialic acid residues, but not meet the claim if NGNA-bearing glycans are calculated as a percentage of total glycan structures.
Accordingly, claim 3 fails to particularly point out and distinctly claim the subject matter which the inventor regards as the invention.
Claim Rejections - 35 USC § 112(a); First Paragraph
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 2, and 4 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The following quotation from section 2163 of the Manual of Patent Examination Procedure is a brief discussion of what is required in a specification to satisfy the 35 U.S.C. 112 written description requirements for a generic claim covering several distinct inventions:
The written description requirement for a claimed genus 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 Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
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, one must describe a sufficient variety of species to reflect the variation within the genus.
Thus, when a claim covers a genus of inventions, the specification must provide written description support for the entire scope of the genus. Support for a genus is generally found where the applicant has provided a number of examples sufficient so that one in the art would recognize from the specification the scope of what is being claimed.
Claims 1, 2, and 4 recite coronavirus-specific human polyclonal immunoglobulin compositions derived from, or methods using, an ungulate. Claim 1 recites an “ungulate-derived polyclonal human immunoglobulin composition” comprising human immunoglobulins that specifically bind coronavirus S, M, E, or N protein. Claim 2 recites a composition “produced by immunizing a transgenic ungulate” with a coronavirus protein or antigenic fragment. Claim 4 recites administering a coronavirus S, M, E, or N protein, antigenic fragment, or encoding polynucleotide to a transgenic ungulate comprising a human immunoglobulin locus or artificial chromosome comprising a human immunoglobulin locus, wherein the ungulate produces the recited coronavirus-binding human immunoglobulins.
The specification describes a transchromosomic bovine system. In particular, Example 1 states that the disclosed Tc bovine production system uses animals in which “bovine Ig genes are knocked-out and a human artificial chromosome (HAC) vector is introduced in the bovine genome to express human polyclonal antibodies.” The example further describes Tc cattle immunized with SARS-CoV-2 spike protein, production of human polyclonal antibodies, collection of plasma, and purification of the Tc bovine-derived human IgG (¶[0182-0186]). The SARS-CoV-2-specific working data likewise concern SAB-185 produced in Tc bovines (¶[0240-0245]). For example, ¶[0242] describes priming “transchromosomic (Tc) bovines” with DNA encoding Wuhan-Hu-1 spike, followed by recombinant spike ectodomain boosts and purification of human IgG SAB-185 from pooled bovine plasma.
However, the scope of claims 1, 2, and 4 is not limited to transchromosomic bovines. The specification expressly defines “ungulate” to include “bovine, pig, horse, donkey, zebra, deer, oxen, goats, sheep, and antelope.”(¶[0082]). Claim 1 therefore encompasses coronavirus-binding human polyclonal immunoglobulin compositions derived from each of those ungulate hosts. Claim 2 encompasses compositions produced by immunizing transgenic forms of those hosts. Claim 4 further encompasses methods using any such transgenic ungulate having either a human immunoglobulin locus in its genome or an artificial chromosome comprising that locus.
The specification names certain nonbovine ungulates and describes selected ungulate-derived components. For example, it identifies bovine, horse, sheep, and pig IgM constant-region sequences (¶[0127]) and also states that a transgenic ungulate having the HAC “is not particularly limited” and identifies cows, horses, goats, sheep, and pigs as possible animals (¶[0130]). Those statements identify possible alternatives, but they do not describe a representative number of functioning nonbovine species that produce the claimed coronavirus-binding human polyclonal immunoglobulin compositions. In particular, the specification does not describe a transgenic horse, pig, sheep, goat, deer, antelope, donkey, or zebra having the claimed human immunoglobulin locus or HAC and producing the recited coronavirus-binding human polyclonal immunoglobulin population, nor does the specification identify structural or biological characteristics common to the full claimed ungulate genus that correlate with the claimed result: production of a human polyclonal immunoglobulin population that specifically binds the recited coronavirus protein. The actual disclosed production system relies on a bovine Ig knockout, a bovine host, bovine plasma collection, and purification of Tc bovine-derived human IgG (¶[0182-0187]).
Claim 1 is broader still because it does not require a transgenic ungulate, a human immunoglobulin locus, an artificial chromosome, a particular genetic configuration, or an immunization regimen. It encompasses an ungulate-derived human polyclonal immunoglobulin composition meeting the recited coronavirus-binding function regardless of the host species or the manner in which that composition was generated. The specification describes Tc bovine-derived SAB-185 directed to SARS-CoV-2 spike protein, but does not describe representative coronavirus-binding human polyclonal immunoglobulin compositions derived from the broader ungulate genus (¶[0182-0186]; [0240-0245]).
The claimed ungulate-derived compositions and methods are defined, at least in part, by the function of producing a population of human immunoglobulins that specifically binds a coronavirus S, M, E, or N protein. However, the specification does not establish a correlation between the disclosed Tc bovine structural features and that functional result sufficient to identify which additional nonbovine ungulate species, host-specific Ig components, genetic modifications, or HAC configurations fall within the scope of the claims. The disclosure of the desired result, together with a working Tc bovine embodiment, does not demonstrate possession of the broader ungulate genus recited in claims 1, 2, and 4.
Accordingly, the disclosure does not reasonably convey to one skilled in the art that the inventor had possession of the full scope of the ungulate-derived compositions and transgenic-ungulate methods recited in claims 1, 2, and 4 at the time of filing.
Claim 3 is rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement. The claim 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 had possession of the claimed invention at the time the application was filed.
Claim 3 recites a polyclonal human immunoglobulin composition comprising a population of human immunoglobulins that specifically binds coronavirus S, M, E, or N protein, or a combination thereof, wherein the immunoglobulins comprise glycans and the glycans comprise at least about 70%, 80%, or 90% NGNA-bearing glycans.
The specification describes glycan analysis of a TcB-derived human immunoglobulin product. Table 6 reports 13.8% “N-glycolyneuraminic (NG)-cont. Structures,” while Table 7 separately reports sialic-acid analysis showing “human IgG from #468” having 0.90 NGNA content (¶[0196-0198]). The specification also describes SAB-185 as an anti-SARS-CoV-2 human immunoglobulin intravenous product purified from plasma of immunized Tc bovines (¶[0216-0217]).
However, claim 3 is not limited to SAB-185, a Tc bovine-derived product, SARS-CoV-2 spike-binding immunoglobulins, a particular sample, a particular production method, or a particular analytical basis for calculating the recited NGNA-bearing glycan percentage. Claim 3 broadly encompasses coronavirus-binding polyclonal human immunoglobulin compositions against S, M, E, or N proteins having the recited NGNA-bearing glycan profile. As set forth in the 35 USC 112b rejection supra, the interpretation of this scope of proteins is very broad, and encompasses any S, M, E, or N protein, and any strain, mutant, or variant thereof, of any coronavirus.
The specification does not describe a representative number of compositions across that scope. The specification also does not identify structural features, production characteristics, or analytical parameters common to the broader claimed group which would allow one skilled in the art to recognize which coronavirus-binding polyclonal human immunoglobulin compositions have the recited NGNA-bearing glycan profile. The disclosure of limited TcB glycan data, together with a separate SARS-CoV-2 product disclosure, does not reasonably convey possession of the full scope of claim 3.
Accordingly, the disclosure does not reasonably convey to one skilled in the art that the inventor had possession of the full scope of the subject matter recited in claim 3 at the time the application was filed.
Claims 1-4 are rejected under 35 U.S.C. 112(a) because the specification, while enabling for production of SARS-CoV-2 Spike protein-specific human polyclonal immunoglobulin in a transchromosomic bovine system, does not reasonably provide enablement for the broader claimed scope of ungulate-derived compositions, any coronavirus protein claimed, and methods using transgenic ungulates. The specification does not enable one skilled in the art to make and use the invention commensurate in scope with these claims.
The legal considerations that govern enablement determinations pertaining to undue experimentation have been set forth in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). The factors include the breadth of the claims, the nature of the invention, the state of the prior art, the level of ordinary skill, the predictability of the art, the direction provided by the specification, the working examples, and the quantity of experimentation needed to practice the claimed invention. The factors are considered as a whole in determining whether any necessary experimentation would have been undue.
Nature of the invention and breadth of the claims. The claimed invention is directed to coronavirus-specific polyclonal human immunoglobulin compositions derived from ungulates, and methods of making such compositions by administering coronavirus antigen to transgenic ungulates. Claim 1 recites an “ungulate-derived polyclonal human immunoglobulin composition” comprising human immunoglobulins that specifically bind coronavirus S, M, E, or N protein, or a combination thereof. Claim 2 recites a polyclonal human immunoglobulin composition “produced by immunizing a transgenic ungulate” with a coronavirus protein or antigenic fragment. Claim 3 recites a polyclonal human immunoglobulin composition comprising a population of human immunoglobulins that specifically binds coronavirus S, M, E, or N protein, or a combination thereof, wherein the immunoglobulins comprise glycans and the glycans comprise at least about 70%, 80%, or 90% NGNA-bearing glycans. Claim 4 recites administering a coronavirus S, M, E, or N protein, antigenic fragment, or polynucleotide encoding the antigen to a transgenic ungulate having a human immunoglobulin locus or an artificial chromosome comprising a human immunoglobulin locus.
The specification describes a particular transchromosomic bovine system. The application states that Applicant developed a Tc bovine production system in which “bovine Ig genes are knocked-out and a human artificial chromosome (HAC) vector is introduced into the bovine genome.” The Tc cattle are then immunized with targets such as SARS-CoV-2 spike ectodomain to produce antigen-specific human polyclonal antibodies (Example 1 starting at ¶[0182]). The working production example uses qualified Tc bovines immunized first with plasmid DNA encoding wild-type SARS-CoV-2 spike protein and then with recombinant SARS-CoV-2 spike protein (¶[0183-0185]). The resulting human IgG is recovered from Tc bovine plasma using bovine-specific depletion and purification steps (¶[0186]).
However, the claims are not limited to that system. The specification defines “ungulate” to include bovine, pig, horse, donkey, zebra, deer, oxen, goats, sheep, and antelope (¶[0082]). The specification further states that a transgenic ungulate having the HAC “is not particularly limited” and identifies cows, horses, goats, sheep, and pigs as possible hosts (¶[0130]).
Claim 1 reaches a coronavirus-binding human polyclonal immunoglobulin composition derived from any of those ungulates, without requiring a Tc bovine, bovine Ig-gene knockouts, a particular HAC, a particular immunization regimen, or a particular purification route. Claim 2 reaches compositions produced by immunizing any transgenic ungulate, without reciting the human Ig-locus configuration or host-specific genetic modifications needed to obtain the claimed human immunoglobulin composition. Claim 4 is narrower in requiring a human immunoglobulin locus or human artificial chromosome (HAC),but still reaches each transgenic ungulate species and multiple antigen forms, including S, M, E, or N protein, antigenic fragments, and encoding polynucleotides. Claim 4 does not specify the system in which the polyclonal antibodies are made, but the glycosylation patterns noted inherently are directed to production in a non-human system, with the same breadth of any of the claimed proteins from any coronaviruses being the target of said polyclonal antibodies.
The claimed scope therefore extends well beyond the disclosed Tc bovine/SARS-CoV-2 spike embodiment.
State of the prior art and predictability of the art. At the time of filing, a person of ordinary skill knew how to generate certain transchromosomic livestock and assess antigen-specific antibody responses. The prior art, however, also showed that successful production of fully human polyclonal immunoglobulin in a large animal depended on host-specific genetic design rather than routine substitution of one ungulate for another.
Kuroiwa et al. (Kuroiwa Y, et al. Nat Biotechnol. 2002 Sep;20(9):889-94. Epub 2002 Aug 12.) describes production of transchromosomic calves using a human artificial chromosome carrying unrearranged human heavy-chain and lambda-chain loci. The human artificial chromosome (HAC) was transferred into bovine primary fetal fibroblasts by microcell-mediated chromosome transfer, followed by primary selection, production of cloned bovine fetuses, secondary selection, and production of four healthy Tc calves. This reference demonstrates that the starting bovine platform itself required extensive species-specific cell engineering, selection, and cloning work.
Matsushita et al. (Matsushita H, et. al. PLoS One. 2015 Jun 24;10(6):e0130699.) further reports that early Tc cattle had low fully human IgG production because human and bovine Ig-production machinery was not functionally interchangeable. The authors state that “species-specific sequence differences” in pre-BCR/BCR components and IgG1 class-switch regulatory elements were “functionally distinct across the two species.” To improve bovine output, the authors used bovinized IgM regions and bovine class-switch regulatory sequences. The reference therefore indicates that successful human Ig production depended on resolving interspecies incompatibilities in the bovine host, not merely introducing a generic human Ig locus into an animal.
The prior art is not devoid of nonbovine transgenic animal work. Wu et al. (Wu H, et. al. Sci Rep. 2019 Jan 23;9(1):366.) describes a separate transchromosomic goat system, but the reference does not establish a general ungulate rule. Rather, the authors describe a new Tc caprine project “building upon” the Tc cattle platform, in which a HAC was introduced into goat fetal fibroblasts followed by somatic cell nuclear transfer to produce Tc goats. The Tc goats were then separately evaluated for human Ig expression and H7N9-specific neutralizing activity following an H7N9/HA1 immunization program. This work supports that another species may be developed through a dedicated caprine system; it does not show that horses, pigs, sheep, deer, zebras, donkeys, antelope, or other ungulates would predictably function using the disclosed bovine system.
Accordingly, the prior art does not support extrapolation from the disclosed Tc bovines to the full ungulate genus recited in the claims. The art instead indicates that host-specific Ig signaling, class-switch regulation, endogenous Ig loci, fetal-cell handling, chromosome transfer, and cloning conditions may materially affect whether a transgenic ungulate can produce the required human polyclonal immunoglobulin composition.
Level of skill in the art. One skilled in the art would have been familiar with molecular cloning, microcell-mediated chromosome transfer, somatic cell nuclear transfer, transgenic-animal production, immunization protocols, antibody purification, ELISA, and neutralization assays. Those techniques permit a person of skill in the art to create and test candidate systems.
However, the availability of those techniques does not establish that one skilled in the art would know which host species, host-specific Ig sequences, class-switch elements, endogenous-locus modifications, human artificial chromosome (HAC) configurations, or immunization conditions would yield a human polyclonal immunoglobulin population meeting the limitations of the claims. The relevant inquiry is not whether candidates could be made and tested, it is whether the specification provides sufficient guidance to identify and practice operative embodiments across the full claimed ungulate genus without undue experimentation.
Working examples. The specification provides working examples directed to one host platform: transchromosomic bovines. Example 1 is expressly directed to “Production of Human Polyclonal Immunoglobulin in Transchromosomic Bovine (TcB) System.”(¶[0181-0186]). The disclosed Tc bovines use bovine Ig-gene knockouts and a human artificial chromosome (HAC) introduced into the bovine genome (¶[0182]). The coronavirus-specific production work also concerns Tc bovines and SARS-CoV-2 spike antigen. The application describes priming Tc bovines with DNA encoding Wuhan-Hu-1 spike protein, followed by recombinant spike ectodomain boosts, and then pooling and purifying Tc bovine plasma to obtain SAB-185 (¶[0183-0186]).
The specification does not provide a working example in a transgenic horse, pig, sheep, goat, deer, zebra, donkey, antelope, or other nonbovine ungulate. Nor does it provide working production data for a human polyclonal immunoglobulin composition generated in those species after administration of coronavirus M protein, E protein, N protein, an antigenic fragment thereof, or a polynucleotide encoding such antigen, or other anti-coronavirus polyclonal antibody compositions with the glycosylation percentages claimed.
Guidance in the specification. The specification provides generalized guidance concerning possible host species and possible ungulate-derived components. For example, the application identifies bovine, horse, sheep, and pig IgM constant-region sequences (¶[0127]). It also identifies bovine, horse, and pig class-switch regulatory elements as exemplary alternatives (¶[0123]). That guidance does not explain how to select or combine those host-specific components so that a particular nonbovine ungulate will maintain the human locus or HAC, support human B-cell development, undergo productive class switching, and yield a coronavirus-specific human polyclonal immunoglobulin composition. The specification does not provide a host-specific rule correlating a selected ungulate IgM constant region or class-switch regulatory element with successful human immunoglobulin production in the corresponding host.
The application states that the transgenic ungulate “is not particularly limited,” but that conclusion is broader than the actual teaching (¶[0130]). The disclosure does not explain whether the bovine Ig-gene knockouts used in the Tc bovine system are required in each nonbovine species, whether the bovine-style HAC modifications are suitable for another host, or which host-specific genetic changes are necessary when bovine components are replaced. The specification notes that the human polyclonal compositions generated in the Tc bovine systems against SARS-CoV-2 S fragment antigens generates glycosylation percentages and patterns claimed, but it is unclear if other ungulate systems or other non-ungulate systems can generate such polyclonal mixtures.
Quantity of experimentation necessary. To practice the full scope of claims 1, 2, and 4, one skilled in the art would need to select an untested ungulate host and establish a functioning human Ig production system in that host. That would require more than administering a known antigen and measuring antibody binding. For each untested species, the skilled artisan would need to determine whether endogenous Ig genes require modification, whether a human Ig locus or HAC is retained and expressed, whether host-specific constant regions or class-switch elements are needed, and whether the resulting animal produces a sufficient population of human immunoglobulins. The skilled artisan would then need to immunize the resulting animals with one or more coronavirus antigens, recover serum or plasma, purify the human immunoglobulins, test the glycosylation patterns, and determine whether the product satisfies the claimed coronavirus-binding limitation.
Such work would not merely involve routine application of known assays to embodiments reasonably expected to work. The cited art shows that the outcome depends on species-specific compatibility between human Ig components and host-animal biology. Although individual engineering and testing methods were known, the specification does not provide sufficient guidance to identify which nonbovine ungulate systems will produce the claimed coronavirus-specific human polyclonal immunoglobulin compositions without undue experimentation.
Amgen. The Supreme Court has explained that a specification need not describe with particularity how to make and use every embodiment within a claimed class. However, the disclosure must enable one skilled in the art to make and use the full scope of the claimed invention. A reasonable amount of experimentation may be permissible depending on the nature of the invention and the underlying art. Amgen Inc. v. Sanofi, 598 U.S. 594, 610-13 (2023).
Here, the specification describes a Tc bovine system using bovine Ig-gene knockouts, a bovine-compatible HAC configuration, and SARS-CoV-2 spike immunization. The claims encompass materially broader polyclonal and/or ungulate-derived compositions and methods using diverse transgenic ungulate hosts. The specification does not identify a general quality or provide sufficient guidance allowing one skilled in the art to practice that broader scope without undue experimentation.
Conclusion. For the reasons discussed above, the specification does not enable one skilled in the art to make and use the full scope of the invention recited in claims 1-4 without undue experimentation.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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.
Claims 1-4 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Luke et. al. (Luke T, et. al. Sci Transl Med. 2016 Feb 17;8(326):326ra21.; CITED ART OF RECORD; hereafter “Luke”) as evidenced by Kuroiwa et. al. (Kuroiwa Y, et. al. Nat Biotechnol. 2009 Feb;27(2):173-81. Epub 2009 Jan 18.; CITED ART OF RECORD; hereafter “Kuroiwa”.)
The Prior Art
Luke teaches human polyclonal IgG generated from sera collected from transchromic (Tc) bovines vaccinated against Middle East respiratory syndrome coronavirus (MERS CoV) with either whole inactivated virions or S proteins, and that the Tc bovines have genome knock-outs of bovine Ig genes and carry a human artificial chromosome (HAC) composed of the entire germline loci of human Ig heavy chain and k light chain which allow them to produce fully human polyclonal IgG antibodies (up to 15 g/liter) and can be bioengineered to have an IgG1 subclass bias (entire document; see abstract; p. 2, left col. ¶2; instant claims 1-2). As evidenced by Kuroiwa, these transchromic cows inherently produce glycosylated human IgG (Fig. 3), which is predominantly NGNA (Fig. 3, p. 177, left col., ¶2; instant claim 3). Luke teaches the cows were vaccinated on five separate occasions every 21 to 28 days (p. 2, rt. col., ¶1). Luke teaches the spike protein used for vaccination was a recombinant glycoprotein that was codon-optimized (p. 6, left col., ¶4). Luke also teaches the cows were vaccinated in pharmaceutical compositions comprising SAb’s proprietary adjuvant formulation (SAB-adj-1)(p. 6, left col., ¶5; instant claim 4).
In summary, Luke teaches every limitation of instant claims 1-4, and anticipates the instant invention.
Claims 1-4 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by SAb Biotherapeutics (SAb Biotherapeutics, Inc. ClinicalTrials.gov. NCT04469179: Safety, Tolerability, and Pharmacokinetics of SAB-185 in Ambulatory Participants With COVID-19. 07/13/2020.; CITED ART OF RECORD; hereafter “SAb Biotherapeutics.”) as evidenced by Liu et. al. (Liu Z, et. al. Hum Vaccin Immunother. 2021 Jul 6:1-10. Epub ahead of print.; CITED ART OF RECORD; hereafter “Liu”.)
The Prior Art
SAb Biotherapeutics teaches SAB-185, an Anti-SARS-CoV-2 Human Immunoglobulin Intravenous (transchromosomic [Tc] bovine-derived), as a potential therapeutic to treat COVID-19 (“Brief Summary”). SAb Biotherapeutics teaches that SAB-185 is a purified human immunoglobulin G (hIgG) that was purified from the plasma of immunized Tc bovines that were immunized initially (vaccinations 1 and 2) with a plasmid DNA (pDNA) vaccine that expresses wild-type SARS CoV-2 spike (S) protein, followed by additional immunizations (vaccinations 3 and beyond) with a recombinant S protein from SARS CoV-2 produced in insect cells (“Arms and Interventions”; instant claims 1-2).
As evidenced by Liu, the SAB-185 composition was generated by common inventors and assignees of the instant claims, and the disclosure of the method of generation of SAB-185 appears to be the same, as well as the vaccination and data acquired (entire document; see esp. “Method details”, Fig. 2 vs. Fig. 8, Fig. 3 vs Fig. 9 of instant invention.) Therefore, absent evidence to the contrary, it is assumed the “proprietary SAB adjuvant” (p. 3, left col., ¶1) comprises MONTANIDE ISA 206 and/or Quil A, and the SAB-185 composition of SAb Biotherapeutics and those of the instant examples would comprise the fucosylation patterns and glycans as provided for in instant claim 3. Further, as evidenced by Liu, the SAB-185 composition maintains the ability to neutralize SARS CoV-2 strains which comprise D614G, S477N, E484K, and N501Y mutations in the S protein (pp. 1-2, ¶ bridging pages), and was generated in Tc bovines that carry a human artificial chromosome (HAC) vector that allows the Tc bovines the ability to generate human IgG antibodies (“Materials and Methods: Tc Bovines”; instant claim 4).
For at least these reasons, it is the opinion that SAb Biotherapeutics teaches, either explicitly or inherently, the entire invention as instantly claimed, and anticipates instant claims 1-4.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-4 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 5 of U.S. Patent No. 11,975,066 B2. Although the claims at issue are not identical, they are not patentably distinct from each other because both the reference claims of ‘066 and instant claims (e.g. claim 4) recite a method of making polyclonal human immunoglobulin for treatment of a coronavirus disease (e.g. COVID-19) by administering a coronavirus antigen (e.g. a polynucleotide encoding a full-length SARS-CoV-2 spike protein) to a transgenic ungulate, wherein the transgenic ungulate comprises a human Ig loci or HAC, wherein the transgenic ungulate produces a population of antibodies against said coronavirus antigen. Both sets of claims are drawn to polyclonal human immunoglobulin compositions produced by immunizing a transgenic ungulate with a coronavirus protein or antigenic fragment thereof. The composition recited in instant claims 1 and 2 is the product produced by, or at least an obvious product of, the claimed method of ‘066. Both sets of claims are drawn to polyclonal human immunoglobulin compositions comprising a population of human immunoglobulins that comprises at least about 70% NGNA-bearing glycans.
The differences between the instant claims and the patented claims amount to broadening or restating the same subject matter in composition and method form. The patented claims recite a narrower Tc bovine/SARS-CoV-2 spike method and glycan-defined product population, while the instant claims attempt to claim broader ungulate-derived compositions, product-by-process compositions, glycan-defined compositions, and transgenic-ungulate methods that include, or would have been obvious over, the subject matter of the patented claims.
Accordingly, claims 1-4 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 5 of U.S. Patent No. 11,975,066 B2.
Prior Art of Record
Within and up to a year from the effective filing date of the instant application, multiple public disclosures appear to have been generated regarding a composition which comprises ungulate-derived (bovine- or cow-derived) polyclonal human immunoglobulins which bind to severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) spike (S) protein, namely a composition colloquially known as “SAB-185”. A comprehensive list of those disclosures is provided in the attached Appendix; while the Office has, in good faith, attempted to compile every public disclosure of SAB-185, the Office acknowledges that there may be other SAB-185 disclosures not yet of record. As noted similarly in the parent application, this SAB-185 appears to be an Applicant-originated composition related to the instant claims.
With respect to disqualifying these disclosures, 37 CFR 1.130(a) discusses an “appropriate affidavit or disclosure to disqualify a disclosure as prior art by establishing that the disclosure was made by the inventor or a joint inventor.” This rule focuses on disqualifying a particular disclosure, and there is no way, as noted in the parent application, to provide a “blanket disclosure” that would cover any and all qualifying prior art disclosures of SAB-185. In other words, the Applicant cannot provide a declaration/affidavit which states that “Every grace-period disclosure of SAB-185 originated with us.”
MPEP §717.01(a)(1) is consistent with the reading of 37 CFR 1.130(a). It gives several factors to consider when evaluating a 1.130(a) declaration – for example, it requires that the declaration give “a reasonable explanation of the presence of additional authors” on the disclosure. MPEP §717.01(a)(1) also instructs:
“The evidence necessary to show that the disclosure is by the inventor or a joint inventor or another who obtained the subject matter disclosed from the inventor or a joint inventor requires case-by-case analysis, depending upon whether it is apparent from the disclosure itself or the patent application specification that the disclosure is an inventor originated disclosure.”
The requirement for “case-by-case analysis”, as noted in the parent application, has convinced the Office that not only does each disclosure have to be accounted for individually, but also despite Applicant’s previously submitted attribution evidence in the parent application concerning some of the same references, that said references may still be applied in the continuation application if it otherwise qualifies as prior art and no sufficient 37 CFR 1.130(a) declaration is of record in the present application. If the same attribution facts apply to the noted references in the Appendix or utilized in any prior art rejection, that evidence may again disqualify the relied-upon disclosure as prior art once properly made of record or otherwise considered.
Again, the Office has attempted in the interest of compact prosecution to provide as comprehensive of a list as possible so that Applicant may, if applicable, attempt to disqualify the noted references as prior art.
Conclusion
No claims are allowed.
As noted supra, the prior art made of record and not relied upon is considered pertinent to applicant's disclosure and is listed in an Appendix attached to this Office action.
As the list is quite extensive, it is being attached as an Appendix to this Office action and constitutes the most comprehensive list of prior art disclosures related to SAB-185-related materials that the Office has been able to compile. If the art is already of Record, it is noted in this file; if the art is not of record, it has been added to the attached PTO-892 and a copy provided herewith.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RACHEL B GILL whose telephone number is (571)272-3129. The examiner can normally be reached on M to F 8:00 AM to 5:00 PM Eastern.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Michael Allen can be reached on (571) 270-3497. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/RACHEL B GILL/
Primary Examiner, Art Unit 1671
Prosecution Insights