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 .
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. However, CN 202110968141.2, filed August 23, 2021, is not a certified English copy. Therefore, the claims are examined with the effective filing date of August 23, 2022 – the filing date of PCT/CN2022/114250.
Claim Objections
Claim 29 is objected to because of the following informalities: the word “and” is missing from line 3. It should read “said antibody specifically binds IL-1b and comprises the following VH and VL:”. Additionally, the word “or” is missing at the end of line 9. In other words, the word “or” is needed to separate VH and VL pair (f) from VH and VL pair (g). Moreover, “SEQ ID NO.” in lines 4-10 should be “SEQ ID NO:” (with a colon, not a period).
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
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 27 and 29 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.
Claims 27 and 29 are indefinite and interpreted as reciting an antibody produced by the method of claim 14 and the antibody of claim 27 which binds to IL-1b.
The breath of claims 27 and 29 is enormous. Claim 27 claims any antibody resulting from claim 14. Claim 14 could administer any mutant antigen resulting in a vast number of antibodies which bind any antigen administered in claim 14. Further, claim 14 recites administering in an animal – any animal – so the resulting antibodies could have constant regions of any species. Claim 29 recites the antibody binds IL-1b, but again this claims a vast number of antibodies which bind IL-1b – any epitope, any species. Furthermore, claims 27 and 29, based on their dependency to the method of claim 14, recite a product-by-process. MPEP 2113 states that product-by-process claims are not limited to the recited steps – only the implied structure. Essentially, the claims are drawn to any antibody and any antibody which binds to IL-1b, respectively. Thus, the claims recite two genera: 1. An antibody that binds any antigen in claim 27 and 2. An antibody which binds IL-1b in claim 29.
One skilled in the art also cannot visualize or recognize the identities of the members of these genera that exhibit these functional properties (binding any antigen or binding to IL-1b). The characteristics defining these genera of antibodies that bind any antigen or bind to IL-1b are unknown as this only sets forth what the antibodies do and not what they are. One would need to conduct further testing to see whether a given antibody was a member of these genera.
The claim scope is potentially enormous depending on how many of the products that meet the structural requirements (being antibodies) would also meet the functional requirements (binding any antigen or binding to IL-1b); by contrast, the scope of the description which includes only seven species of anti-IL-1b antibodies (see pages 22-23), is extremely narrow. Furthermore, the specification fails to disclose sufficient identifying characteristics of the genera, as discussed in more detail below.
Furthermore, regarding the species of antibody which bind IL-1b, AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc., No. 13-1338 (Fed. Cir. 2014) opined “[o]ne factor in considering the question is how large a genus is involved and what species of the genus are described in the patent. If the genus is not large or, even if it is, the specification discloses species representing the genus throughout its scope, the requirement may be met. […] Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the genus”.
Indeed, the species of anti-IL-1b antibodies taught in the instant application are not representative of the genus through its scope. All anti-IL-1b antibodies disclosed were obtained by immunizing mice with human IL-1b, see page 27, yet the scope of claim 29 encompasses any anti-IL-1b antibody obtained by immunizing any animal with IL-1b of any species. This even genus of anti-IL1b antibodies encompasses camelid single domain antibodies which the instant Specification does not teach.
It is true that functionally defined claims can meet the written description requirement if a reasonable structure-function correlation is established, whether by the inventor as described in the specification or known in the art at the time of the filing date. Enzo Biochem, Inc. v. Gen-Probe Inc., 323 F.3d 956, 964 (Fed. Cir. 2002). However, the record here does not indicate such an established correlation. The claims attempt to claim every antibody that would achieve a desired result, i.e. binding any antigen or binding to IL-1b. However, the instant application only describes seven anti-IL-1b antibodies per se. The specification fails to identify what structural features would be responsible for conferring these desired properties and as such, fails to disclose a correlation between structure and function. Furthermore, even if the Specification established a structure-function correlation, the structure is not required by the claims.
Thus, one of ordinary skill in the art would not conclude that Applicant was in possession of the two genera: 1. An antibody that binds any antigen in claim 27 and 2. An antibody which binds IL-1b in claim 29.
Claim Rejections - 35 USC § 112(b)
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 1-3, 5, 6, 8, 9, 13-17, 19, 20, 21, 23, 25, 27, 29, and 31 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.
Claims 1, 13, and 14, recite “a derivative thereof”. First, it is unclear if “thereof” refers back to the mutant antigen or the group with chemical cross-linking activity. Second, both the group with chemical cross-linking activity and the mutant antigen, which is interpreted as comprising the group with chemical cross-linking activity, are defined not by a structure, but by functions (ie. the potential to generate an immune response and chemical cross-linking activity). It is unclear what derivatives of either the group with chemical cross-linking activity and the mutant antigen, which is interpreted as comprising the group with chemical cross-linking activity, or their associated functions (ie. the potential to generate an immune response and chemical cross-linking activity) would be.
Claim 1 recites the “mutant antigen, which is incorporated with a group with chemical cross-linking activity”. It is unclear if the mutant antigen is a mutant because of the addition of the group with chemical cross-linking activity. Or does the claim require that the antigen have other mutations rendering it mutant antigen and also the group with chemical cross-linking activity? To be clear, the phrase “mutant antigen, which is incorporated with” is the cause of confusion. Is the antigen mutated, then the group with chemical cross-linking activity is added? . For the purpose of compact prosecution, the limitation “mutant antigen, wherein the mutant antigen is formed by incorporating a group with chemical cross-linking activity into a target epitope of a wild-type antigen”. This language more closely matches the definition of mutant antigen on page 14 of the Specification and clarifies that the incorporation of the group with chemical cross-linking activity is the reason for the categorization of “mutant” – not that the antigen is mutated and, then, the group with chemical cross-linking activity is incorporated.
Similarly, claims 13 and 14 recites “the mutant antigen is incorporated by chemical cross-linking reactive groups or derivatives thereof on the target epitope of the wild-type antigen” or “the mutant antigen in incorporated with a group with chemical cross-linking activity or its derivative thereof on the target epitope of the wild-type antigen”. Claims 13 and 14 suffer the same indefiniteness as claim 1; see above. For the purpose of compact prosecution, claims 13 and 14 are interpreted as “mutant antigen, wherein the mutant antigen is formed by incorporating a group with chemical cross-linking activity into one or more target epitopes of a wild-type antigen”.
Further, claim 13 recites the limitation "the wild-type antigen" in line 4. There is insufficient antecedent basis for this limitation in the claim. For the purpose of compact prosecution, “the wild-type antigen” of line 4 is interpreted as referring back to “an antigen” in line 2.
Claim 1 recites “an agent”. Merriam-Webster defines agent as “something that produces or is capable of producing an effect : an active or efficient cause” or “a chemically, physically, or biologically active principle.” Yet, the claim then recites two components: 1. The mutant antigen and 2. A physiologically acceptable carrier. A carrier is understood in the art to be a passive dilutant – not “a chemically, physically, or biologically active principle.” It is unclear, since the preamble recites an agent, whether the passive “physiologically acceptable carrier” is actually required? For the purpose of compact prosecution, claim 1 is interpreted as reciting a composition comprising a mutant antigen and a carrier.
Additionally, claim 1 recites and “immunologically effective amount of a mutant antigen” in line 2 and “wherein the agent stimulates or enhances the production of antibodies against the one or more target epitopes in vivo after being administered to the animal” in lines 6 and 7. Indeed, stimulating an immune response is an inherent property of an antigen, but recitation of “immunologically effective amount” combined with the active voice of “stimulates or enhances” and the phrase “in vivo after being administered” causes indefiniteness. Is claim 1 claiming the composition / the thing or the method of administering the composition? For the purpose of compact prosecution, claim 1 is interpreted as claiming a composition comprising a mutant antigen and carrier, “wherein the composition is capable of stimulating or enhancing the production of antibodies against one or more target epitopes in an animal” – the wherein clause being an inherent property of the mutant antigen.
Regarding claims 2, 20, 29, and 31, the word "preferably" renders the claim indefinite because it is unclear whether the limitations following "preferably" are part of the claimed invention. See MPEP § 2173.05(d). For the purpose of compact prosecution, the claims are interpreted as not requiring any of the limitations that follow “preferably”.
Regarding claim 16, the phrase "as well as" 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). Additionally, if parts (iii) and (iv) of claim 16 are required, it is unclear whether they are required only with the second set of (i) and (ii) are performed or whether they are required when either set of parts (i) and (ii) are performed. For the purpose of compact prosecution, the claim is interpreted as requiring parts (iii) and (iv) when either set of (i) and (ii) is performed.
Claim 16 recites “under certain conditions”. The word certain here suggests that the conditions under which incubation and elution occur are specific; see Merriam-Webster definition of ‘Certain’. However, it is unclear what specific conditions are being claimed. In other words, the phrase “certain conditions” in the method conveys that those particular conditions are critical to the method - one would not be carrying out the claimed method if not conducted within those “certain conditions”. For the purpose of compact prosecution, “certain condition” is interpreted as any condition.
Similarly, claim 13 recites administering a “certain amount”. The word certain here suggests that the amount administered is specific; see Merriam-Webster definition of ‘Certain’. One administering an amount differing from that certain amount would not be performing the claimed method. It is unclear what amount is required to be administered. For the purpose of compact prosecution, “certain amount” is interpreted as any amount.
Claim 14 step (a) recites the verb “providing a mutant antigen” which indicates giving or making the mutant antigen available to someone else or something else. It is unclear how one would give away the mutant antigen, but then still be in possession of it to be able to administer the mutant antigen to an animal in step (b). For the purpose of compact prosecution, claim 14 step (a) is interpreted as obtaining or producing the mutant antigen.
Claim 27 recites "the antibody obtained by the method according to claim 14" in the first line. There is insufficient antecedent basis for this limitation in the claim. Claim 14 is recites a method of immunizing an animal with a modified antigen. The immunization of an animal with an antigen would result in the generation of a number of antibodies against the antigen. It is unclear which particular antibody (“the antibody”) is claimed in claim 27. For the purpose of compact prosecution, “the antibody” is interpreted as reciting “an antibody obtained by the method according to claim 14”.
Claims 2, 3, 5, 6, 8, and 9 are rejected for depending from claim 1 and failing to remedy the indefiniteness.
Claims 17 and 19 are rejected for depending from claim 16 and failing to remedy the indefiniteness.
Claims 20, 21, 23, and 25 are rejected for depending from claim 13 and failing to remedy the indefiniteness.
Claims 15-17, 19, 27, 29, and 31 are rejected for depending from claim 14 and failing to remedy the indefiniteness.
Claim 29 is rejected for depending from claim 27 and failing to remedy the indefiniteness.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 8 and 9 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 8 recites that “the agent [interpreted as referring to the composition of claim 1] is an agent for antibody production.” Claim 9 recites that “the agent [interpreted as referring to the composition of claim 1] is a prophylactic or therapeutic agent”. Claims 8 and 9 recite intended use of the claimed composition of claim 1 and fail to further limit the composition claimed.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Interpretation
All independent claims recite a group with chemical cross-linking activity. Page 14 of the Specification recites “ ‘chemical cross-linking’ means that a group having chemical cross-linking activity can covalently cross-link with a group of amino acids residues adjacent to a protein under suitable conditions.” “A protein” here is not explicitly defined, but the claims recite the group having chemical cross-linking activity being incorporated into an antigen, so “a protein” is interpreted as an antigen. The definition recites covalently binding amino acid residues “adjacent to a protein”. Adjacent means next to something, so next to or nearby the antigen, but not within the antigen.
In summary, a group with chemical cross-linking activity is interpreted as a group which can covalently bind the antigen into which it is incorporated with another protein.
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 (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.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 2, 5, 6, 8, and 9 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Chen et al. (Science Advances. 6: eaaz7825; Published: April 1, 2020) as evidenced by the IL-1beta Safety Data Sheet (Enzo Life Sciences. Product ALX-522-056; Published: April 4, 2013).
Regarding claims 1, 2, and 5, Chen et al. teaches incorporating the noncanonical amino acid p-benzoyl-L-phenylalanine (pBpa) by codon expansion into the target epitope of IL-1b; see ‘Incorporation of an ncAA with photocrosslinking reactivity in the target epitope’ section. Regarding the carrier in claim 1, Chen et al. teaches that the proteins with pBpa incorporated with purified in DPBS buffer – a physiologically acceptable carrier. Regarding claim 6, the IL-1beta SDS evidences that IL-1b is a soluble protein.
Regarding claim 8, the target epitope of human IL-1b with pBpa incorporated is an agent for antibody production because Chen et al. demonstrates that immunization of Balb/c mice with human IL-1b will result in antibody production. Regarding claim 9, the target epitope of human IL-1b with pBpa incorporated can be used as a therapeutic because it will elicit an immune response and can be used to treat conditions associated with elevated IL-1b.
Thus, Chen et al. as evidenced by the IL-1beta Safety Data Sheet anticipates claims 1, 2, 5, 6, 8, and 9.
Claims 1, 2, 5, 6, 8, 9, 13-15, 20, 23, 27 and 31 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Fiorentini et al. (Vaccine. 26: 4758-4765; Published: July 9, 2008).
Regarding claims 1, 2, and 5, Fiorentini et al. teaches developing a peptide-based vaccine against HIV-1 comprising a synthetic peptide (AT20) which was synthesized (ie. chemical synthesis) with the addition of N-Leu and Cys at the C-terminus; see ‘2.2. Synthesis of peptide’ section. The carrier protein KLH was cross-linked through the added, natural amino acid, Cys residue. Regarding the physiologically acceptable carrier of claim 1, the AT20-Cys-KLH protein was emulsified in incomplete Freund’s adjuvant; see ‘2.3. Immunization protocol’ section. Also, KLH is a carrier protein (see first paragraph of page 4759) and physiologically acceptable to use when eliciting and antibody generating response. There is no limiting definition for the limitation “physiologically acceptable carrier” in the instant disclosure.
Regarding claims 6, 8, 9, 13, 14, 20, 23, and 31, the AT20-Cys-KLH peptide was used to immunized Balb/c mice which elicited antibody production and neutralized hp17/p17R interaction (ie. was a prophylactic against HIV-1 infection); see ‘2.3. Immunization protocol’ section and second paragraph of page 4759.
Regarding claim 15, the serum from the mice was collected and the reactivity of sera was tested against p17, the wild-type antigen, by solid-phase ELISA; see ‘2.3. Immunization protocol’ section.
Regarding claim 27, the immunization of Balb/c mice with AT20-Cys-KLH peptide resulted in the production of antibodies; see ‘3.5. Neutralization of p17/p17R interaction by anti-AT20 Abs’ section.
Thus, Fiorentini et al. anticipates claims 1, 2, 5, 6, 8, 9, 13-15, 20, 23, 27 and 31.
Claims 1, 2, 5, 6, 8, 9, 13-15, 20, 23, 25, 27, and 31 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Tsao et al. (CN 101970005 A; Published: February 9, 2011) as evidenced by Escrieut et al. (Journal of Biological Chemistry. 277 (9): 7546-7555; Published: March 1, 2002).
Regarding claims 1 and 2, Tsao et al. teaches an immunogen comprising an added unnatural or non-natural amino acid to the target part or epitope; see claim 1 and page 120. Of non-natural amino acids, Tsao et al. exemplifies the incorporation of p-nitro-phenylalanine (pNO2Phe), but teaches several non-natural amino acids, including derivatives of amino acids with reactive side chains such as Lys, Cys, and Tyr; see pages 138, 150-158 and 173. Tsao et al. teaches adding a non-natural amino acid which interact covalently with another molecule; see page 152. As evidenced by Escrieut et al., pNO2Phe has covalent crosslinking activity when treated with UV; see page 7554. Regarding the carrier of claim 1, Tsao et al. teaches the fusion of the immunogen with a carrier protein, for example KLH, or with a carrier such as a buffer; see page 181. Mice were immunized with 5 μg of protein in 200 μl of PBS was mixed 1:1 with complete Freund's adjuvant (CFA) for the first injection or with incomplete Freund's adjuvant (IFA) 1:1 for the remaining 6 injections; see page 196.
Regarding claim 5, Tsao et al. teaches incorporating pNO2Phe to Tyr 86 of murine TNF-alpha by codon expansion; see page 189.
Regarding claims 6 and 25, TNF-alpha is a soluble protein; see page 143.
Regarding claims 8 and 9, Tsao et al. states “we show that immunization of mice with the murine tumor necrosis factor-α (mTNFα) Tyr 86 → pNO2Phe mutant produces high titers of antibodies in response to WT mTNFα and thus effectively protects mice against lipopolysaccharide (LPS) stimulation; see page 189.
Regarding claims 13, 14, 20, 23, 27, and 31, mice were immunized with murine tumor necrosis factor-α (mTNFα) Tyr 86 → pNO2Phe mutant protein; see page 196.
Regarding claim 15, serum was isolated from the immunized mice and antibody titers against pNO2Phe-mTNF-alpha and wild-type mTNF-alpha were determined by ELISA; see page 197.
Thus, Tsao et al. as evidenced by Escrieut et al. anticipates claims 1, 2, 5, 6, 8, 9, 13-15, 20, 23, 25, 27, and 31.
Claims 27 and 29 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Xia et al. (US 11,976,115 B2; Filed: November 4, 2019; Published: May 7, 2024).
Claims 1-14 of Xia et al. teach an anti-IL-1b antibody. Example 1 of Xia et al. teaches that the antibody was generated by immunization of mice.
Claims 27 and 29 recite any antibody or any anti-IL-1b antibody, respectively, generated by the method of claim 14 which comprises administering the mutant antigen to an animal. MPEP 2113 (III) states that “We are therefore of the opinion that when the prior art discloses a product which reasonably appears to be either identical with or only slightly different than a product claimed in a product-by-process claim, a rejection based alternatively on either section 102 or section 103 of the statute is eminently fair and acceptable.”
Thus, Xia et al. anticipates claims 27 and 29.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 16, 17, 18, and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Tsao et al. (CN 101970005 A; Published: February 9, 2011) as evidenced by Escrieut et al. (Journal of Biological Chemistry. 277 (9): 7546-7555; Published: March 1, 2002) as applied to claim(s) 1, 2, 5, 6, 8, 9, 13-15, 20, 23, 25, 27, and 31 above, and in view of Chen et al. (Science Advances. 6: eaaz7825; Published: April 1, 2020).
The teachings of Tsao et al. as evidenced by Escrieut et al. as related to claim(s) 1, 2, 5, 6, 8, 9, 13-15, 20, 23, 25, 27, and 31, from which these claims depend are given previously in this Office action and are fully incorporated here.
While Tsao et al. teaches obtaining the serum of immunized mice and assessing antibody titers, the reference does not teach constructing an antibody library, using the mutant antigen to cross-link to reactive antibodies, then releasing then to assess specificity with the wild-type antigen.
Regarding claim 16, Chen et al. teaches constructing a phage library using the spleens of immunized mice or using B cells from human peripheral blood mononuclear cells; see ‘Epitope-directed selection against a human naïve antibody phage library’ and ‘Construction of phage display library’ sections. Chen et al. teaches incubating phages with a mutant antigen, IL-1b with p-benzoyl-L-phenylalanine (pBpa), and treating with UV radiation. Regarding claims 16 and 17, antibodies not covalently bound are washed with an acidic (low-pH) buffer, and covalently linked antibodies are removed by trypsin digestion; see ‘Epitope-directed selection against a human naïve antibody phage library’ section and Figure 2. Regarding claim 16 step (iv), Chen et al. teaches harvesting the phages which covalently bound and assessing the binding affinities to both WT IL-1b and the IL-1b-pBpa mutant antigen; see ‘Hit picking and analysis’ section.
Both Tsao et al. and Chen et al. teach mutant antigens with groups with chemical cross-linking activity which covalently bind adjacent amino acids when treated with UV radiation. Because of this similarity between the groups with chemical cross-linking activity taught by Tsao et al. and Chen et al., it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to use the method taught by Chen et al. of screening an antibody library obtained from the mice immunized in Tsao et al. for binding to the mutant antigen, treating with UV, then washing in acidic conditions, and releasing covalently bound antibodies with trypsin. Additionally, because Chen et al. teaches further assessing the binding affinities of the antibodies obtained from this screening or panning method to both the mutant antigen and the wild-type antigen, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to further assess the binding affinity of the obtained antibodies to the wild-type antigen.
Moreover, regarding claim 29, because both Tsao et al. and Chen et al. use cytokines as the basis for the mutant antigens, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to modify the method of Tsao et al. to immunize mice with a mutant antigen comprising IL-1b to obtain anti-IL-1b antibodies.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Claims 3 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Tsao et al. (CN 101970005 A; Published: February 9, 2011) as evidenced by Escrieut et al. (Journal of Biological Chemistry. 277 (9): 7546-7555; Published: March 1, 2002) as applied to claim(s) 1, 2, 5, 6, 8, 9, 13-15, 20, 23, 25, 27, and 31 above, and further in view of Furman et al. (Journal of the American Chemical Society. 136: 8411-8417; Published: May 20, 2014).
The teachings of Tsao et al. as evidenced by Escrieut et al. as related to claim(s) 1, 2, 5, 6, 8, 9, 13-15, 20, 23, 25, 27, and 31, from which these claims depend are given previously in this Office action and are fully incorporated here.
Tsao et al. teaches incorporating a non-natural amino acid into an antigen to elicit an immune response, but the reference does not teach that the non-natural amino acid is Nε-acryloyl-L-lysine (AcrK) or Nε-crotonyl-L-lysine (Kcr).
Furman et al. teaches that AcrK is an unnatural amino acid which resulted in covalent protein to protein crosslinking; see pages 8411, 8412, and 8416 for example.
Given that Tsao et al. teaches that derivatives of lysine may be used to generate mutant antigens and asserts that the key to eliciting an immune response to a self-antigen is the incorporation of a non-natural amino (see claim 1 and pages 120, 138, 150-158 and 173), it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success substituting one the various non-natural amino acids to be incorporated with the antigen as taught by Tsao et al. with the non-natural amino acid, AcrK, and immunizing a mouse with the mutant antigen to generate an immune response against the self-antigen as taught by Tsao et al.
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.
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Claims 1, 2, 5, 6, 8, 9, 13-17, 19, 20, 23, 25, 27, and 31 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-26 of copending Application No. 17/800,229 in view of Tsao et al. (CN 101970005 A; Published: February 9, 2011) as evidenced by Escrieut et al. (Journal of Biological Chemistry. 277 (9): 7546-7555; Published: March 1, 2002).
Regarding instant claims 1 and 2, copending claims 1-26 teach a method of selecting or screening antibodies against a target antigen. Copending claims 1, 12, 13, 17, 20, and 22 teach an mutant antigen wherein an amino acid with photocrosslinking activity has been incorporated and that amino acid is non-canonical pBpa or pAzF.
Regarding instant claim 5, copending claim 2 teaches incorporation by genetic expansion.
Regarding instant claim 6, copending claims 11, 18, 21, 24, and 26 teach that the antigen of the mutant antigen is a soluble protein, a cell surface protein, or a transmembrane protein.
Regarding instant claims 8 and 9, a mutant antigen comprising an amino acid with photocrosslinking activity would be expected to produce antibodies because that is an inherent property of antigens. Further, because antigens, including the mutant antigen, can elicit the production of antibodies, a composition comprising the mutant antigen may be used as a prophylactic or therapeutic agent.
Regarding instant claims 16 and 17, copending claims 1-26 teach methods of selecting antibodies comprising contacting the antibodies with a mutant antigen under conditions that allow for photocrosslinking, and elution under acidic or alkaline conditions to remove non-covalently linked antibodies. Regarding instant claim 19, copending claim 16 teaches releasing covalently bound antibodies by enzymatic digestion.
The copending claims do not teach a physiologically acceptable carrier, immunizing an animal, isolating serum, using wild-type antigen to select antibodies from serum, or constructing an antibody library from isolating B cells.
Regarding claims 1 and 2, Tsao et al. teaches an immunogen comprising an added unnatural or non-natural amino acid to the target part or epitope; see claim 1 and page 120. Of non-natural amino acids, Tsao et al. exemplifies the incorporation of p-nitro-phenylalanine (pNO2Phe), but teaches several non-natural amino acids, including derivatives of amino acids with reactive side chains such as Lys, Cys, and Tyr; see pages 138, 150-158 and 173. Tsao et al. teaches adding a non-natural amino acid which interact covalently with another molecule; see page 152. As evidenced by Escrieut et al., pNO2Phe has covalent crosslinking activity when treated with UV; see page 7554. Regarding the carrier of claim 1, Tsao et al. teaches the fusion of the immunogen with a carrier protein, for example KLH, or with a carrier such as a buffer; see page 181. Mice were immunized with 5 μg of protein in 200 μl of PBS was mixed 1:1 with complete Freund's adjuvant (CFA) for the first injection or with incomplete Freund's adjuvant (IFA) 1:1 for the remaining 6 injections; see page 196.
Regarding claim 5, Tsao et al. teaches incorporating pNO2Phe to Tyr 86 of murine TNF-alpha by codon expansion; see page 189.
Regarding claims 6 and 25, TNF-alpha is a soluble protein; see page 143.
Regarding claims 8 and 9, Tsao et al. states “we show that immunization of mice with the murine tumor necrosis factor-α (mTNFα) Tyr 86 → pNO2Phe mutant produces high titers of antibodies in response to WT mTNFα and thus effectively protects mice against lipopolysaccharide (LPS) stimulation; see page 189.
Regarding claims 13, 14, 20, 23, 27, and 31, mice were immunized with murine tumor necrosis factor-α (mTNFα) Tyr 86 → pNO2Phe mutant protein; see page 196.
Regarding claim 15, serum was isolated from the immunized mice and antibody titers against pNO2Phe-mTNF-alpha and wild-type mTNF-alpha were determined by ELISA; see page 197.
Tsao et al. teaches obtaining antibody titers from serum, but Tsao et al. does not teach a method of screening an antibody library.
While Tsao et al. teaches obtaining the serum of immunized mice and assessing antibody titers, neither Tsao et al. nor the copending claims teach constructing an antibody library from B cells and assessing specificity with the wild-type antigen.
Regarding claim 16, Chen et al. teaches constructing a phage library using the spleens of immunized mice or using B cells from human peripheral blood mononuclear cells; see ‘Epitope-directed selection against a human naïve antibody phage library’ and ‘Construction of phage display library’ sections. Chen et al. teaches incubating phages with a mutant antigen, IL-1b with p-benzoyl-L-phenylalanine (pBpa), and treating with UV radiation. Regarding claims 16 and 17, antibodies not covalently bound are washed with an acidic (low-pH) buffer, and covalently linked antibodies are removed by trypsin digestion; see ‘Epitope-directed selection against a human naïve antibody phage library’ section and Figure 2. Regarding claim 16 step (iv), Chen et al. teaches harvesting the phages which covalently bound and assessing the binding affinities to both WT IL-1b and the IL-1b-pBpa mutant antigen; see ‘Hit picking and analysis’ section.
Given that Tsao et al. teaches immunizing mice with a mutant antigen comprising a self-antigen and an amino acid with photocrosslinking activity and a carrier, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to make a composition comprising the mutant antigen of the copending claims and a carrier. Further, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to immunize an animal with the mutant antigen as taught by Tsao et al. for the purpose of generating an immune response.
The copending claims, Tsao et al. and Chen et al. teach mutant antigens with groups with chemical cross-linking activity which covalently bind adjacent amino acids when treated with UV radiation. Because of this similarity between the groups with chemical cross-linking activity taught by Tsao et al. and Chen et al., it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to use the method taught by Chen et al. of screening an antibody library obtained from the mice immunized in Tsao et al. for binding to the mutant antigen, treating with UV, then washing in acidic conditions, and releasing covalently bound antibodies with trypsin. Additionally, because Chen et al. teaches further assessing the binding affinities of the antibodies obtained from this screening or panning method to both the mutant antigen and the wild-type antigen, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to further assess the binding affinity of the obtained antibodies to the wild-type antigen.
Moreover, regarding claim 29, because both Tsao et al. and Chen et al. use cytokines as the basis for the mutant antigens, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to modify the method of Tsao et al. to immunize mice with a mutant antigen comprising IL-1b to obtain anti-IL-1b antibodies.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
This is a provisional nonstatutory double patenting rejection.
Claim 27 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5, 7, 8, 10-12, 14, 15, 17, 20-22 of copending Application No. 18/692,754 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Claim 27 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 17/778,422 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Claim 27 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 10, 11, 15, 17-27 of copending Application No. 17/287,539 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Claim 27 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 of copending Application No. 17/905,870 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Claim 27 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 4, 5, 8-13, 18, 21, 24-26, 28, 31, 36, 39, 43, 47, and 49 of copending Application No. 18/546,980 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Claim 27 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 29-46 of copending Application No. 18/245,879 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Copending claims 1-3, 5, 7, 8, 10-12, 14, 15, 17, 20-22 of Application No. 18/692,754 teach an anti-HERV-K antibody.
Copending claims 1-20 of Application No. 17/778,422 teach an anti-PSMA antibody.
Copending claims 1-4, 10, 11, 15, 17-27 of Application No. 17/287,539 teach an anti-PD-1 antibody.
Copending claims 1-25 of Application No. 17/905,870 teach anti-CD40 antibodies.
Copending claims 1, 2, 4, 5, 8-13, 18, 21, 24-26, 28, 31, 36, 39, 43, 47, and 49 of Application No. 18/546,980 teach anti-CLDN18.2 antibodies.
Copending claims 29-46 of Application No. 18/245,879 teach anti-HERV-K antibodies.
Claim 27 recites any antibody generated by the method of claim 14 which comprises administering the mutant antigen to an animal. MPEP 2113 (III) states that “We are therefore of the opinion that when the prior art discloses a product which reasonably appears to be either identical with or only slightly different than a product claimed in a product-by-process claim, a rejection based alternatively on either section 102 or section 103 of the statute is eminently fair and acceptable.”
Thus, the copending claims of Application No. 18/692,754; 17/778,422; 17/287,539; 17/905,870; 18/546,980; and 18/245,879 read on instant claim 27 in an anticipatory manner.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 27 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of U.S. Patent No. 9,243,055 B2. Although the claims at issue are not identical, they are not patentably distinct from each other.
Claim 27 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 9,644,021 B2. Although the claims at issue are not identical, they are not patentably distinct from each other.
Claim 27 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 10,259,863 B2. Although the claims at issue are not identical, they are not patentably distinct from each other.
Issued claims 1-6 of U.S. Patent No. 9,243,055 B2 teach anti-HERV-K antibodies.
Issued claims 1-19 of U.S. Patent No. 9,644,021 B2 teach bovine antibodies.
Issued claims 1-12 of U.S. Patent No. 10,259,863 B2 teach bovine antibodies.
Claim 27 recites any antibody generated by the method of claim 14 which comprises administering the mutant antigen to an animal. MPEP 2113 (III) states that “We are therefore of the opinion that when the prior art discloses a product which reasonably appears to be either identical with or only slightly different than a product claimed in a product-by-process claim, a rejection based alternatively on either section 102 or section 103 of the statute is eminently fair and acceptable.”
Thus, the issued claims of U.S. Patent No. 9,243,055 B2; 9,644,021 B2; and 10,259,863 B2 read on instant claim 27 in an anticipatory manner.
Potentially Allowable Subject Matter
No claims are currently allowed.
The following is a statement of reasons for the indication of allowable subject matter: An anti-IL-1b antibody comprising the VH and VL pairs recited in claim 29 are novel and nonobvious over the prior art.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Zhao (CN 107080837 B; Published: November 6, 2020) teaches labeling tumor cell antigens with non-natural sugars or non-natural amino acids containing azide groups so that the tumor cell surface antigens incorporate the azide groups, cross-linking biotin with the azide groups incorporated into the tumor cell surface antigens by bioorthogonal reaction, and finally cross-linking with the ligand IgG1Fc of a specific phagocytic receptor comprising avidin; see claim 1.
Xie et al. (Clinical Rheumatology. 41:3851-3858; Published: August 8, 2022) Nε-crotonyl-L-lysine (Kcr) promotes antigen binding to MHC II molecules; see Abstract.
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/KATHERINE ANN HOLTZMAN/Examiner, Art Unit 1646
/JULIET C SWITZER/Primary Examiner, Art Unit 1682
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