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 .
It appears the inventor filed the current application pro se (i.e., without the benefit of representation by a registered patent practitioner). While inventors named as applicants in a patent application may prosecute the application pro se, lack of familiarity with patent examination practice and procedure may result in missed opportunities in obtaining optimal protection for the invention disclosed. The inventor(s) may wish to secure the services of a registered patent practitioner to prosecute the application, because the value of a patent is largely dependent upon skilled preparation and prosecution. The Office cannot aid in selecting a patent practitioner.
A listing of registered patent practitioners is available at https://oedci.uspto.gov/OEDCI/. Applicants may also obtain a list of registered patent practitioners located in their area by writing to Mail Stop OED, Director of the U.S. Patent and Trademark Office, P.O. Box 1450, Alexandria, VA 22313-1450.
In addition, Applicant is encouraged to contact the Application Assistance Unit (AAU), which unit can provide assistance with a broad range of questions and issues. The AAU is available Monday – Friday from 8:30 AM to 5:00 PM (Eastern). AAU contact information: 888-876-0101 (Toll Free) or 571-272-4000 (Local).
Election/Restrictions
Applicant's election with traverse of Group VIA in the reply filed on September 14, 2025 is acknowledged.
The traversal is on the ground(s) that the search burden is not serious and that the groups should be organized differently.
This is not found persuasive because each of the groups is classified differently and the groups are not obvious variants of each other. Thus, because the groupings are deemed to be correct the burden to search each of the groups is deemed be undue.
In addition, Dr. Roger Swartz filed a supplemental response to the Requirement for Restriction on December 3, 2025, in which the election was clarified to be Group VI, as a whole, encompassing claims 33-37.
However, under further consideration, Group I is rejoined with elected Group VI, and will be considered at this time. Therefore, claims 1-7, 9-11, 14-20, and 32-37 are under consideration at this time. Claims 8, 12, 21 and 23-31 are withdrawn from consideration at this time, as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on December 3, 2025. It is noted that claims 13 and 22 are canceled.
The remainder of the requirement is still deemed proper and is therefore made FINAL.
Information Disclosure Statement
Applicants provided an Appendix to the Specification, listing 27 pages of references. In addition, the Specification itself contains additional references. However, the listings of references in the specification are not proper information disclosure statements. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Drawings
Applicant omitted Figures 5 and 33. However, Applicants claim priority to U.S. Provisional Patent Application Nos. 63/060,300; 63/076,527; 63/214,612, with the ‘527 application including Figures 5 and 33. If Applicant provides a statement that these three provisional applications are incorporated by reference in their entirety, the ‘527 application can be relied upon to provide reintroduction of Figures 5 and 33 (see below in § Specification).
Nucleotide and/or Amino Acid Sequence Disclosures
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
Sequences present at page 58 of the specification at lines 1, 2, and 4 do not have the required SEQ ID NOS.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specification
While Applicant claims priority to U.S. Provisional Patent Application Nos. 63/060,300; 63/076,527; 63/214,612, there is no statement to incorporate the subject matter of these provisional patent applications into this application by reference. Applicant is required to amend the disclosure to include the material incorporated by reference, if the material is relied upon to overcome any objection, rejection, or other requirement imposed by the Office. The amendment must be accompanied by a statement executed by the applicant, or a practitioner representing the applicant, stating that the material being inserted is the material previously incorporated by reference and that the amendment contains no new matter. 37 CFR 1.57(g).
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code at pages 9, 47 (2), 82, 83 (2), 125, 130 (2), 131, 132, 133, and 136. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The disclosure is objected to because of the following informalities:
All genus/species names throughout the specification should be italicized.
Each page should have the line numbering beginning at line 1, rather than the line numbering being listed throughout the specification.
At page 132, line 2, “atleast” should be changed to “at least.”
The Tables in the Specification are too small to be legible.
Appropriate correction is required.
Claim Objections
Claims 5-7, 14-20, and 32-37 are objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim cannot depend from any other multiple dependent claim. See MPEP § 608.01(n). Accordingly, these claims have not been further treated on the merits.
Therefore, because claims 8, 12, 21 and 23-31 are drawn to a non-elected invention, because claims 5-7, 14-20, and 32-37 are objected to, and because claims 13 and 22 are canceled, as discussed above, claims 1-4 and 9-11 are under examination on the merits.
Claims 1-4 and 9-11 are objected to because of the following informalities:
At claim 1, line 6, “must be” should be changed to “are.”
At claim 1, line 9, “[c]hain” should be changed to “chain.”
At claim 1, line 13, “and” should be inserted after “system,”.
At claim 1, line 15, “derived” should be changed to “obtained.”
At claim 1, line 18, “Allergens” should be changed to “allergens.”
At claim 1, line 20, “or” should be inserted after “ailment,”.
At claim 2, line 1, “Claim” should be changed to “claim.”
At claim 2, line 4, “in” should be deleted.
At claim 2, line 5, “the vector contains” should be changed to “the vectors contain.”
At claim 2, line 7, “that may be” should be changed to “is.”
At claim 2, line 10, “that may be” should be changed to “is.”
At claim 2, line 15, “The” should be changed to “the.”
At claim 2, line 19, “The” should be changed to “the.”
At claim 2, line 21, “The” should be changed to “the.”
At claim 2, line 22, “a” should be inserted before “first.”
At claim 2, line 27, “The” should be changed to “the.”
At claim 3, line 9, the period after “site” should be deleted.
At claim 3, line 9, “The” should be changed to “the.”
At claim 3, line 10, “the” should be deleted.
At claim 4, lines 2-3, “the vector is” should be changed to “the vectors are.”
At claim 4, line 7, “and’ should be inserted before “a non-viral vector.”
At claim 9, line 5, “derived” should be changed to “obtained.”
At claim 9, line 8, “Allergens” should be changed to “allergens.”
At claim 9, line 17, it is suggested that “derived” be deleted.
At claim 9, lines 20-21, it is suggested that “regardless of whether it is engineered or not” be deleted.
At claim 9, line 26, “vector” should be changed to “vectors.”
At claim 10, line 6, “derived” should be changed to “obtained.”
At claim 10, line 8, “Allergens” should be changed to “allergens.”
At claim 10, line 26, the comma after incorporated should be deleted. If the hyphen is present so that the deletion is intended the comma and the hyphen should be deleted.
At claim 11, line 10, “derived” should be changed to “obtained from.”
At claim 11, line 11, “even” before “plasma” should be deleted.
At claim 11, line 11, “derived” should be changed to “obtained.”
Appropriate correction is required.
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.
Claims 1 and 9-10 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed by him. The courts have stated:
To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997); In re Gostelli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) ("[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious" and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966; Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
Further, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents of the University of California v. Eli Lilly & Co., the court stated:
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. Fiers v. Revel, 984 F.2d at 1171,25 USPQA2d, 1601; In re Smyth, 480 F.2d 1376,1383, 178 USPQ 279,284 (CCPA 1973) ("In other cases, particularly but not necessarily, chemical cases, where there is an unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus...") Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The MPEP further states that if a biomolecule is described only by a functional characteristic, without any disclosed correlation between function and structure of the sequence, it is "not a sufficient characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence." MPEP § 2163. The MPEP does state that, for a generic claim, the genus can be adequately described in the disclosure presents a sufficient number of representative species that encompass the genus. MPEP § 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP § 2163. Although the MPEP does not define what constitutes a sufficient number of representative species, the courts have indicated what does not constitute a representative number of species to adequately describe a broad genus. In Gostelli, the courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gostelli, 872 F.2d at 1012, 10 USPQ2d at 1618. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include: (1) Actual reduction to practice, (2) Disclosure of drawings or structural chemical formulas, (3) Sufficient relevant identifying characteristics (such as: i. Complete structure, ii. Partial Structure, iii. Physical and/or chemical properties, iv. Functional characteristics when coupled with a known or disclosed structure, and v. Correlation between function and structure), (4) Method of making the claimed invention, (5) Level of skill and knowledge in the art, and (6) Predictability in the art.
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. This disclosure of only one or a few species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure indicates that the patentee has invented species sufficient to constitute the gen[us]." See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 115; Noelle v. Lederman, 355 F.3d, 1343, 1350, 69 USPO2d 1508, 1514 (Fed. Cir. 2004) ("[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated."). In addition, it has been well known that minor structural differences even among structurally related compounds can result in substantially different biology, expression, and activities. The instant claims require that the IgG and IgA memory B-cells are derived from the blood of persons previously exposed to, has immune specificity to, or are affected by one or more of viruses, allergies, allergens, fungi, bacterial infection, cancer, an unnatural virus or toxin, microbial infection, any ailment, a target protein or variants including self-antigens. The rejected claims thus comprise a genus of afflictions that provide IgG or IgA memory B-cells being obtained from blood of subjects. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of a complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, and any combination thereof. The specification states that “[e]pression of dIgA1 and dIgA2 and derivatives of dIgA1 and dIgA2 from mRNA, an episome or genomic DNA via retroviral incorporation of a retroviral vector such as on delivered by a lentivirus or gammaretrovirus is claimed in this instant patent.” See paragraph bridging pages 13 and 14. However, it is impossible for one to extrapolate from the generic recitation of broad classes of afflictions that provide for immune specificity would be useful from which IgG and IgA can be obtained. The prior art does not appear to offset the deficiencies of the instant specification. The prior art teaches that B cells in rejection and tolerance is unpredictable, stating that there is incomplete understanding about the heterogeneity of injury response in organ transplantation (abstract). Further, the disparate mechanistic roles of B cells in organ injury have been increasingly recognized (Zarkhin et al., 24 Seminars in Immunology 86-91 (2012)).Thus, the specification is not sufficient to support the broadly claimed genus of afflictions of subjects from which IgG and IgA B-cells are obtained.
The description of the limited sources of IgG and IgA memory B-cells is not sufficient to support the genus of B-cell sources. Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed.” (See Vas-Cath at page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is now is claimed." (See Vas-Cath at page 1116). As discussed above, the skilled artisan cannot envision the detailed chemical structure of the encompassed genus of B-cell sources, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation or identification. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18USPQ2d 1016. Therefore, the skilled artisan would have reasonably concluded applicants were not in possession of the claimed invention for claims 1 and 9-10
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 1-4 and 9-11 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.
At claim 1, line 3, it is not clear if the information in the parentheses is intended to be a claim limitation or not. It is suggested that “(immunoglobulins)” be deleted.
Claim 1 recites the limitation "the episome" in line 7. There is insufficient antecedent basis for this limitation in the claim. It is suggested that “the episome” be changed to “the episomal expression vector.”
Claim 1 recites the limitation "the polypeptide sequence" in lines 7-8. There is insufficient antecedent basis for this limitation in the claim. It is suggested that “the” be changed to “a.”
Regarding claim 1, the phrase "including" at line 20 renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 2, the phrase "including" at line 2 renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
At claim 2, line 8, the phrase “B-cell of interest” is indefinite because what cell is of interest to one practitioner might not be of interest to a different practitioner. It is suggested that “of interest” be deleted.
At claim 2, line 11, the phrase “B-cell of interest” is indefinite because what cell is of interest to one practitioner might not be of interest to a different practitioner. It is suggested that “of interest” be deleted.
Claim 2 recites the limitation "the subsequent transgene" in lines 7-8. There is insufficient antecedent basis for this limitation in the claim. It is suggested that “the” be changed to “a.”
Claim 2 recites the limitation "the second transgene" in line 23. There is insufficient antecedent basis for this limitation in the claim. It is suggested that “the” be changed to “a.” Such an amendment will also correct the antecedent basis for “the second transgene” at lines 24-25.
Regarding claim 2, the phrase "such as" at lines 29-30 renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 2 recites the limitation "the cis acting elements" in line 24. There is insufficient antecedent basis for this limitation in the claim. It is suggested that “the” be deleted.
Claim 3 recites the limitation "the transgenes" in line 3. There is insufficient antecedent basis for this limitation in the claim. It is suggested that “the” be deleted.
Claim 3 recites the limitation "the immunoglobulin heavy chain IgH" in line 3. There is insufficient antecedent basis for this limitation in the claim. It is suggested that “the” be changed to “an.”
Claim 3 recites the limitation "the immunoglobulin light chain" in lines 3-4. There is insufficient antecedent basis for this limitation in the claim. It is suggested that “the” be changed to “an.”
Regarding claim 4, the phrase "such as" at line7 renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 9 recites the limitation "the source" in line 12. There is insufficient antecedent basis for this limitation in the claim. It is suggested that “the source in” be deleted.
Claim 9 recites the limitation "the potent immunoglobulin" in line 12. There is insufficient antecedent basis for this limitation in the claim. It is suggested that “the” be changed to “a.” In addition, the term “potent” is a relative term, and without a comparator, the claim is indefinite.
Claim 9 should be rewritten so that the claim is one sentence, rather than the three sentences presently in the claim (see lines 15 and 25).
Regarding claim 9, the phrase "for example" (e.g.) at line 22renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
At claim 10, line 3, it is not clear if the information in the parentheses is intended to be a claim limitation or not. It is suggested that “(immunoglobulins)” be deleted.
At claim 10, line 13, the terms “moderate to high associated constant” are relative terms, and without a comparator, the claim is indefinite.
Claim 10 recites the limitation "the protein of interest" in lines 13-14. There is insufficient antecedent basis for this limitation in the claim. It is suggested that “the” be changed to “a.” In addition, the phrase “protein of interest” is indefinite because what protein is of interest to one practitioner might not be of interest to a different practitioner. It is suggested that “of interest” be deleted.
Claim 10 recites the limitation "the nucleotides" in line 26. There is insufficient antecedent basis for this limitation in the claim. It is suggested that “the” be deleted.
At claim 11, line 2, it is not clear if the information in the parentheses is intended to be a claim limitation or not. It is suggested that “(immunoglobulins)” be deleted.
Claim 11 should be rewritten so that the claim is one sentence, rather than the four sentences presently in the claim (see lines 6, 20, and 25).
At claim 11, line 13, the term “potent” is a relative term, and without a comparator, the claim is indefinite.
At claim 11, line 15, the term “potent” is a relative term, and without a comparator, the claim is indefinite.
Claim 11 recites the limitation "the same vector" in line 22. There is insufficient antecedent basis for this limitation in the claim. It is suggested that “the same vector” be changed to “a single vector.”
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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)(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.
Claims 1, 4, and 9-10 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Rawlings et al. (PCT Patent Application Publication No. WO 2019/241721, published December 19, 2019).
Regarding claim 1, Rawlings discloses episomal expression, genomic integrated lentiviral vector, or gammaretroviral vector-based expression of mRNA expression of monoclonal or polyclonal antibodies (paragraphs [00296], [00300], and [00449]). Rawlings discloses that the antibodies can be of one or more of isotypes, including IgA, or class, including IgA1, IgA2, IgG1, IgG2, IgG3, and dlgA1, as well as polymeric immunoglobulins A1, dIgA1, IgA1, dlgA2, and A2, (paragraphs [00169] and [00192]). Rawlings discloses that episome, genomic integrated lentiviral vector, or mRNA encodes for a polypeptide sequence for immunoglobulins light and heavy chains, in which VH and VL domains are expressed, as well as a J-chain (paragraphs [0023 and [00214]). Rawlings discloses that the J chain allows for joining of the pentameric immunoglobulin structures and therefore is forming dimeric IgA1 and IgA2 that is expressed in the same cell (paragraphs [00124] and [00207]). Rawlings discloses that the cell is identified from one or more of CD27+ IgG memory B-cells, CD27+ IgA memory B-cells, any memory B-cell, memory plasma B-cell, plasma B- cells, plasmablasts, cells from any transgenic animal, cells from a mouse or rabbit with a humanized immunized system, or from a mouse other non-human vertebrate antibody converted into a chimeric antibody (paragraphs [00071]-[00072]). Rawlings discloses that the IgG memory B-cells can be derived from the blood of persons or animals who are currently infected with, were previously infected, were previously exposed to, have immune specificity to, or affected by one or more of a virus or a plurality of viruses, a systemic ailment such as allergies, allergens, fungi, bacterial infection, cancerous tumor, an unnatural virus or toxin, a microbial infection, any ailment, a target protein, or variant including self-antigens that comprises or expresses the antigen of interest (paragraphs [00072]-[00073] and [00078]).
Regarding claim 4, Rawlings discloses construction of viral vectors, retroviral vectors, non-viral vectors, or mRNA vectors selected from one or more of the group consisting of an adeno-associated virus (AAV) vector, an AAV vector, an adenovirus viral vector, a self-inactivating replication-incompetent lentivirus retroviral vector, a self-inactivating replication-incompetent gammaretroviral vector, a self-inactivating lentiviral vector, a self-inactivating gammaretroviral vector, a non-viral vector, and an mRNA vector (paragraph [00298]).
Regarding claim 9, Rawlings discloses the episomal, genomic integrated lentiviral vector or gammaretroviral vector, or mRNA expression of monoclonal antibody polypeptide sequence or polyclonal antibody polypeptide sequence for VH and VL immunoglobulin light and heavy chains (paragraphs [00298], [00300], and [00449]). Rawlings discloses that IgG and IgA B-cells (paragraph [00124]) are derived from blood of persons or animals who are currently infected with, were previously infected, were previously exposed to, has immune specificity to, or affected by one or more of a virus or a plurality of viruses, a systemic ailment such as allergies, allergens, fungi, bacterial infection, cancerous tumor, an unnatural virus or toxin, any ailment, a target protein, or variant, an immune system protein such as immunoglobulin class E (IgE) or a cytokine that comprises or expresses the antigen of interest (paragraph [[00072]-00073], [00078]). Rawlings discloses that the antibodies can be modified in the following ways: V-regions are coded for as were identified from the source in the cell expressing a potent immunoglobulin or one or more of VL and VH may optionally have one or more of the Complementary Determining Regions (CDR) or Framework regions (FR) modified or replaced with another FR region (paragraphs [00373] and [00376]). Rawlings discloses that one or more of the domains of the immunoglobulin heavy chain constant domains consisting of CH1, hinge, and CH2 are replaced by one or more of natural human derived constant regions to reduce immunogenicity and/or modulate effector functions, engineered constant regions to modulate effector functions, and/or adding a furin cleavage site residue to C-terminal end of the immunoglobulin heavy chain (paragraphs [0010], [00214]-[00215]). Rawlings discloses that CH3 should be derived from IgA1 or IgA2, regardless of whether it is engineered or not and that the immunoglobulin light chain's constant regions (CL) is optionally added or modified by one or more of changing type ( kappa (κ) to lambda (λ)) or lambda (λ) to kappa (κ)), such that the light chain can be a kappa chain or a lambda chain (paragraph [00192]). Rawlings further discloses that additional modifications include adding a furin cleavage site residue on the C-terminal end, modifying the hinge length, modifying the hinge amino acids or amorphous chain amino acids, where the dIgA immunoglobulins use immunoglobulin heavy and light chains identified from a single IgA and through incorporating J-chain into the vector where the J-chain may optionally be modified by adding a furin cleavage site to its C-terminal end (paragraphs [00023] and [00207]).
Regarding claim 10, Rawlings discloses the episomal, genomic integrated lentiviral vector, gammaretroviral vector, or mRNA expression of monoclonal antibody polypeptide sequence or polyclonal antibody (immunoglobulin) polypeptide sequence for VH and VL. immunoglobulin light and heavy chains (paragraphs [00298], [00300], and [00449]). Rawlings discloses previously identified potent immunoglobulins where IgG and IgA B-cells are derived from the blood of persons or animals who are currently infected with or were previously infected with, exposed to or affected by one or more of a virus, a systemic ailment such as but not limited to allergies, allergens, fungi, bacterial infection, cancerous tumors, an unnatural virus or toxin, any ailment, a target protein or variant, or an immune system protein such as immunoglobulin class E (IgE) or a cytokine (paragraphs [00072]-[00073] and 00078]). Rawlings discloses that the immunoglobulins can be modified , with an IgG1, IgG3, IgA1, IgA2, dlgA1 or dlgA2 immunoglobulin identified to be of moderate to high association constant against the protein of interest may be modified by generating the dlgA1 or dlgA2 recombinant isotype of that immunoglobulin by using the dlgA1 or dlgA2 heavy chain constant region to replace the constant region of the parent immunoglobulin (paragraphs [00103], [00193, 00194]). Rawlings discloses that the resulting dlgA1 or dlgA2 antibody where the J chain allows for joining of the pentameric immunoglobulin structures and forming dimeric IgA1 and IgA2 (paragraph [00207]). Rawlings discloses that the antibodies may be modified by engineering the constant domains to modify Fe receptor binding with mutagenesis techniques or with mixes of two constant regions from two isotypes or subclasses that may be modified by replacing one or more of the CH1, hinge or CH2 regions with one or more of one or more of the CH1, hinge, or CH2 regions respectively as a one-to-one correspondence of replacement (paragraph [00215]) or by replacing the Fab or F(ab')2-as identified from the B-cell with the dlgA1 or dlgA2 Fab or F(ab')2 respectively (paragraph [00215]).
Rawlings discloses each and every limitation of claims 1, 4, and 9-10, and therefore Rawlings anticipates claims 1, 4, and 9-10.
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.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Rawlings et al. (PCT Patent Application Publication No. WO 2019/241721, published December 19, 2019), as applied to claims 1, 4, and 9-10 above.
Rawlings discloses expression of monoclonal and polyclonal antibodies, as discussed above.
Rawlings does not disclose or suggest sequencing the expression antibodies and antibody fragments using sequencing protocols.
Regarding claim 11, Rawlings discloses an episomal, genomic integrated lentiviral vector or gammaretroviral vector, or mRNA expression vector (paragraphs [00298, 00300[) of polyclonal or monoclonal antibodies (paragraph [00449]) immunoglobulins) based on one or more of dlgA1 and dlgA2 (paragraphs [00207], [00298], and [00300]). Rawlings discloses the J-chain allows for joining of the pentameric immunoglobulin structures, thereby forming dimeric IgA1 and IgA2 (dlgA1 and dlgA2) (paragraph [00207]). Rawlings discloses that both the VH and VL regions are expressed (heavy chain and light chain) (paragraph [00214]). Rawlings discloses that the antibody binding fragments (Fab) are identified or derived from single chain variable fragments {scFv) or Fab from combinatorial libraries, produced by a Fab expression library (paragraphs [00102] and [00191]). Rawlings discloses that the expression is assessed by phage display technology; where scFv is used to identify VI and VL fragments (paragraph [00102]). Rawlings discloses that the VL and VH polypeptides are joined by a linker polypeptide (paragraphs [00185] and [00493]). Rawlings discloses that the polypeptides are used for the formation in one or more of dlgA1 and dIgA2, with the J-chain allowing for joining of the pentameric immunoglobulin structures thereby forming dimeric IgA1 and IgA2 (paragraph [00207]). Rawlings discloses polymeric immunoglobulin digA1 and/or dIgA2 produced by random recombination and shuffling with optional mutagenesis of human VH and VL regions of scFv from human antibody libraries derived from different human B-cells including, naive B-cells, memory B-cells, and plasma secreting B-cells used to identify potent immunoglobulin VH and VL regions pairs that may be used to recombine the VL with the constant regions of the immunoglobulin light chain and combining the VH regions with any of the constant region of IgA1 and IgA2 (paragraphs [00102], [00191], and [00207]). Rawlings discloses modified hinge variants that may be used to reduce immunogenicity to produce engineered dimeric immunoglobulins of one or more of dlgA1 and dlgA2 from the same vector and as a result of 2A self-processing peptides cleavage/ribosomal skip (paragraphs [00102], [00191], and [00207]).
Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used sequencing to identify Rawlings’ VH or VL of the scFv because this is a well-known molecular biology technique that is employed to determine the identity of expressed sequences, including antibody and immunoglobulin sequences. Because the technique is so well-known, one of ordinary skill in the art would have been motivated to identify the immunoglobulin fragments in an accurate and reproducible manner.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Rawlings et al. (PCT Patent Application Publication No. WO 2019/241721, published December 19, 2019), as applied to claims 1, 4, and 9-10 above, and in view of Fang et al. (15(6) Molecular Therapy 1153-1159 (2007)).
Regarding claim 3, Rawlings discloses an mRNA, viral vector, non-viral vector or retroviral vector coding for any one of IgG1, IgG2, IgG3, IgA1, or IgA2, the vector containing in any order of the transgenes for the immunoglobulin heavy chain IgH, the immunoglobulin light chain that may be kappa (lgLκ) or lambda (IgLλ) (paragraphs [00169] and [00192]) as determined from B cell clones, as discussed above (paragraphs [00298, 00300], and [00345]).
Rawlings does not disclose that the vector comprises, in the 5' to 3' direction, a promoter operably linked to the two transgenes expressed as a single open reading frame where each transgene is separated from the subsequent transgene in the 5' to 3' direction by a furin cleavage site, a sequence encoding a 2A self-processing cleavage site or that the vector comprises in the 5' to 3' direction the use of separate promoters and polyadenylation elements for each transgene.
Fang discloses opportunities for delivery of therapeutic monoclonal antibodies in the clinic (abstract). Fang discloses a vector comprising in the 5' to 3' direction a promoter operably linked to the two transgenes expressed as a single open reading frame where each transgene is separated from the subsequent transgene in the 5' to 3' direction by a furin cleavage site (page 1153, column 1 and 2, first paragraph of "Introduction" section). Fang discloses the expression of full-length two-chain antibodies from a single open reading frame (ORF) by linking the heavy and light antibody chains with a 2A self-processing sequence and a furin cleavage site, a sequence encoding a 2A self-processing cleavage site; or the vector comprising in the 5' to 3' direction the use of separate promoters and polyadenylation elements for each transgene with the optional use of a woodchuck hepatitis virus posttranscriptional regulatory element (WPRE) to precede one or more polyadenylation elements (page 1153, column 1 and 2, first paragraph of "Introduction" section).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the vector construct as disclosed by Rawlings to incorporate the ORF, as disclosed by Fang, to provide the benefit of regulated high-level expression of native full-length mAbs in vivo and to offer a new opportunity for delivery of therapeutic mAbs in the clinic.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Rawlings et al. (PCT Patent Application Publication No. WO 2019/241721, published December 19, 2019), in view of Fang et al. (15(6) Molecular Therapy 1153-1159 (2007)), as applied to claims 1, 3-4, and 9-10 above, and further in view of Baliga et al. (U.S. Patent Application Publication No. 2021/0087273, published March 25, 2021 and claiming priority to U.S. Patent Application No. 16/827,100, filed March 23, 2020, now U.S. Patent No. 10,899,835, PCT Patent Application No. PCT/US2019/020374, filed March 1, 2019, and U.S. Provisional Patent Application No. 62/637,186, filed March 1, 2018).
Regarding claim 2, Rawlings discloses a B-cell of interest and mRNA, viral, non-viral, or retroviral vectors, including lentiviral vectors, hybrid adenoviral vectors, and herpes simplex viral vectors, and gammaretroviral vectors (paragraphs [00298, 00300]-[00301], and [00345]). Rawlings discloses that these vectors can code for one or more of dimeric immunoglobulin Al (dIgA1). and/or dlgA2 (paragraphs [00169. 00192]). Rawlings discloses that the vector contains the transgenes in any order for an immunoglobulin light chain that may be kappa (IgLκ) or lambda (IgLλ) (paragraph [00192]) as determined from gene sequencing of the B-cell of interest in claim 1 (paragraph [00345]) and J-chain (paragraph [0023]) or an immunoglobulin light chain that may be kappa (IgLκ) or lambda (IgLλ) (paragraph [00192]) as determined from the B-cell and J chain, where the immunoglobulin light and heavy chains encoded for in any nucleic acid vector were expressed by the same B-cell (paragraph [00124]).
Fang discloses opportunities for delivery of therapeutic monoclonal antibodies in the clinic (abstract). Fang discloses a vector comprising in the 5' to 3' direction a promoter operably linked to the two transgenes expressed as a single open reading frame where each transgene is separated from the subsequent transgene in the 5' to 3' direction by a furin cleavage site (page 1153, column 1 and 2, first paragraph of "Introduction" section). Fang discloses the expression of full-length two-chain antibodies from a single open reading frame (ORF) by linking the heavy and light antibody chains with a 2A self-processing sequence and a furin cleavage site, a sequence encoding a 2A self-processing cleavage site; or the vector comprising in the 5' to 3' direction the use of separate promoters and polyadenylation elements for each transgene with the optional use of a woodchuck hepatitis virus posttranscriptional regulatory element (WPRE) to precede one or more polyadenylation elements (page 1153, column 1 and 2, first paragraph of "Introduction" section).
Rawlings and Fang do not disclose or suggest immunoglobulin heavy chain of isotype Al (IgHA1 or IgHA2), or that the vector encoding for dIgA1 or dlgA2 comprises in a 5' to 3' direction a promoter operably linked to all transgenes expressed in a single open reading frame where each transgene is separated from the subsequent transgene in the 5' to 3' direction by a furin cleavage site.
Baliga discloses a heavy chain, a light chain, and a J-chain construct, which includes two or more nucleic acid sequences encoding two or more or all three polypeptide subunits (paragraph [0152]). Baliga discloses that the vectors provide for increased serum half-life of the antibody.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the vector construct as disclosed by Rawlings and Fang to incorporate the ORF comprising dimerized antibodies, as Rawlings and Fang disclose IgA1 and IgA2, digA1 or digA2 (dimerized versions), to provide tile benefit of regulated high-level expression of native full-length mAbs in vivo and which provides a new opportunity for delivery of therapeutic mAbs in the clinic, as disclosed by Fang.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the vector construct as disclosed by Rawlings and Fang to incorporate a single construct with the heavy, light, and J-chain, as disclosed by Baliga, to provide the benefit of increased serum half-life upon the antibody.
Conclusion
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NANCY J. LEITH
Primary Examiner
Art Unit 1636
/NANCY J LEITH/Primary Examiner, Art Unit 1636