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 .
Claim Status
Applicant’s preliminary amendments received 17JUN2024 are acknowledged.
Claims 2-45, 64-102, and 104-181 have been canceled.
Claims 47-49, 52, 54-63 and 103 have been amended.
Claims 1, 46-63, and 103 are pending in the instant application (i.e., Claim(s) 1 and 46 is/are independent).
Priority
The present application is a 371 National Stage of PCT International Application No. PCT/US2022/028864, filed 11MAY2022, which claims the benefit of US Provisional Patent Application No. 63/187931, filed 12MAY2021 and US Provisional Patent Application No. 63/288992, filed 13DEC2021. Applicant’s claim for the benefit of prior-filed application is acknowledged.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on 04SEP2024 and 05OCT2023 is/are acknowledged and the references cited therein have been considered.
Specification
The disclosure is objected to because of the following informalities:
Sequences Table contains typographical errors: On p 137, “Ultralong CD3 Antibody…” should be updated to “Ultralong CDR3 Antibody…” as necessitated.
Appropriate correction is required.
Claim Objections
Claims 47-48 are objected to because of the following informalities:
Claims 47-48 contain the phrase “The method of any of claim…” which should be corrected to “The method of claim…” in line 1 of the claims.
Appropriate correction is required.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1, 46, and 48-49 are rejected under 35 U.S.C. 101 because the claimed inventions are not directed to patent eligible subject matter. After consideration of relevant factors with respect to claim(s) 1, 46, and 48-49 as a whole, the claims are directed to laws of nature, nature-based products, and abstract ideas without significantly more. The rationale for this determination is explained below:
Because abstract ideas, laws of nature, and natural phenomenon "are the basic tools of scientific and technological work", the Supreme Court has expressed concern that monopolizing these tools by granting patent rights may impede innovation rather than promote it. See Alice Corp., 573 U.S. at 216, 110 USPQ2d at 1980; Mayo Collaborative Servs. v. Prometheus Labs., Inc., 566 U.S. 66, 71, 101 USPQ2d 1961, 1965 (2012). However, the Court has also emphasized that an invention is not considered to be ineligible for patenting simply because it involves a judicial exception. Alice Corp., 573 U.S. at 217, 110 USPQ2d at 1980-81 (citing Diamond v. Diehr, 450 U.S. 175, 187, 209 USPQ 1, 8 (1981)). Accordingly, the Court has said that integration of an abstract idea, law of nature or natural phenomenon into a practical application may be eligible for patent protection. See, e.g., Alice, 573 U.S. at 217, 110 USPQ2d at 1981 (explaining that "in applying the §101 exception, we must distinguish between patents that claim the ‘buildin[g] block[s]’ of human ingenuity and those that integrate the building blocks into something more" (quoting Mayo, 566 U.S. at 89, 110 USPQ2d at 1971) and stating that Mayo "set forth a framework for distinguishing patents that claim laws of nature, natural phenomena, and abstract ideas from those that claim patent-eligible applications of those concepts"); Mayo, 566 U.S. at 80, 84, 101 USPQ2d at 1969, 1971 (noting that the Court in Diamond v. Diehr found "the overall process patent eligible because of the way the additional steps of the process integrated the equation into the process as a whole." See MPEP §2016.
STEP 1: Is the claim to a process, machine, manufacture, or composition of matter?
Claims 1, 46, and 48-49 are drawn to a process.
[Step 1: Claims 1, 46, and 48-49: yes]
STEP 2A (1st prong): Do the claims recite a judicially-recognized exception (JE), e.g., a law of nature, a natural phenomenon or product, or an abstract idea?
Laws of nature and natural phenomena, as identified by the courts, include naturally occurring principles/relations and nature-based products that are naturally occurring or that do not have markedly different characteristics compared to what occurs in nature. The courts have often described these exceptions using other terms, including "physical phenomena," "scientific principles", "natural laws," and "products of nature." See MPEP §2106.04(b).
Law of Nature recitation in claim 1: “amplifying sequences encoding a plurality of VH regions of the IgHV1-7 family” under BRI this recitation is considered to be a “product of nature” in accordance with University of Utah Research Foundation v Ambry Genetics, 774 F.3d 755-760. In this instance, a plurality of VH regions of the IgHV1-7 family is considered to be a product of nature because the naïve genes utilize germline-encoded immunoglobulin VH genes, which are structurally identical to the naturally occurring gene.
Law of Nature recitation in claim 2: “immunizing a cow with a target antigen” under BRI this recitation is considered to be a “product of nature” in accordance with University of Utah Research Foundation v Ambry Genetics, 774 F.3d 755-760. In this instance, a target antigen is considered to be a product of nature because the target antigen may be a naturally occurring bacteria, virus, protein, etc., which are structurally identical to the naturally occurring bacteria, virus, proteins, etc..
Law of Nature recitation in claim 2: “preparing a VH cDNA template library from RNA isolated from PBMCs from the immunized cow” under BRI this recitation is considered to be “law of nature” in accordance with Mayo Collaborative Servs. V. Prometheus Labs., Inc. In this instance, the PBMCs from the immunized cow from which the library is prepared is considered to be a part of a natural process of immunization.
The abstract idea exception has deep roots in the Supreme Court’s jurisprudence. See Bilski v. Kappos, 561 U.S. 593, 601-602, 95 USPQ2d 1001, 1006 (2010) (citing Le Roy v. Tatham, 55 U.S. (14 How.) 156, 174–175 (1853)). Despite this long history, the courts have declined to define abstract ideas. However, it is clear from the body of judicial precedent that software and business methods are not excluded categories of subject matter. The enumerated groupings are firmly rooted in Supreme Court precedent as well as Federal Circuit decisions interpreting that precedent, as is explained in MPEP § 2106.04(a)(2).
The enumerated groupings of abstract ideas are defined as:
1) Mathematical concepts – mathematical relationships, mathematical formulas or equations, mathematical calculations (see MPEP § 2106.04(a)(2), subsection I);
2) Certain methods of organizing human activity – fundamental economic principles or practices (including hedging, insurance, mitigating risk); commercial or legal interactions (including agreements in the form of contracts; legal obligations; advertising, marketing or sales activities or behaviors; business relations); managing personal behavior or relationships or interactions between people (including social activities, teaching, and following rules or instructions) (see MPEP § 2106.04(a)(2), subsection II); and
3) Mental processes – concepts performed in the human mind (including an observation, evaluation, judgment, opinion) (see MPEP § 2106.04(a)(2), subsection III).
Mental process recitation in claim 48: “identifying the CDR3-knob from the cow antibody VH chain template sequences” under BRI this step is considered an abstract idea in the “mental processes” group. For example, aligning the VH sequences to identify the ultralong HCDR3 motif (i.e., CDR3 starts one amino acid after position 104 and ends one amino acid before position 118 according to IGMT numbering) and then isolating the unique arrangement of an even number of cysteine residues (for example, determine the number of amino acid residues between the cysteine at position 104 to the highly conserved cysteine at position D2 of the DH region and subtract the number of amino acid residues from position 118 to determine the end of the CDR3 knob (i.e., the highly conserved cysteine at position D2 of the DH region is the start of the CDR3-knob and the amino acid residue position that results from subtracting the number of amino acid residues from position 118 is the end of the CDR3-knob) is an act of evaluating information that can be practically performed in the human mind.
Mental process recitation in claim 49: “identifying the conserved cysteine in FW3 and the conserved tryptophan in FW4” under BRI this step is considered an abstract idea in the “mental processes” group. For example, aligning the VH sequences to identify the ultralong HCDR3 motif is an act of evaluating information that can be practically performed in the human mind.
Mathematical concept recitation in claim 49:
“The method of claim 48, wherein the CDR3 knob is identified from an antibody sequence by an algorithm comprising:
Identifying…; and
determining the sequence of the CDR-3 knob, in which:
the CDR-3 knob has the amino acid sequence length K;
the sequence begins at position X+1 and ends at X+K; and
K = L-2X;
wherein L is the number of amino acids in an amino acid sequence starting at the conserved cysteine in framework 3 and ending at the conserved tryptophan in framework 4, and
X is the number of amino acids from the first cysteine in framework 3 to the first conserved cysteine encoded by the DH region in CDR H3” under BRI this step is considered an abstract idea in the “mathematical concept” group.
[Step 2A (1st prong): Claims 1, 46, and 48-49: yes]
STEP 2A (2nd prong): Do the claims recite additional elements that integrate the judicial exception into a practical application?
The Supreme Court has long distinguished between principles themselves (which are not patent eligible) and the integration of those principles into practical applications (which are patent eligible). See, e.g., Mayo Collaborative Servs. v. Prometheus Labs., Inc., 566 U.S. 66, 80, 84, 101 USPQ2d 1961, 1968-69, 1970 (2012) (noting that the Court in Diamond v. Diehr found ‘‘the overall process patent eligible because of the way the additional steps of the process integrated the equation into the process as a whole,’’ but the Court in Gottschalk v. Benson ‘‘held that simply implementing a mathematical principle on a physical machine, namely a computer, was not a patentable application of that principle’’). The Supreme Court and Federal Circuit have identified a number of considerations as relevant to the evaluation of whether the claimed additional elements demonstrate that a claim is directed to patent-eligible subject matter.
Limitations the courts have found indicative that an additional element (or combination of elements) may have integrated the exception into a practical application include:
• An improvement in the functioning of a computer, or an improvement to other technology or technical field, as discussed in MPEP §§ 2106.04(d)(1) and 2106.05(a);
• Applying or using a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition, as discussed in MPEP § 2106.04(d)(2);
• Implementing a judicial exception with, or using a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim, as discussed in MPEP § 2106.05(b);
• Effecting a transformation or reduction of a particular article to a different state or thing, as discussed in MPEP § 2106.05(c); and
• Applying or using the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception, as discussed in MPEP § 2106.05(e).
The courts have also identified limitations that did not integrate a judicial exception into a practical application:
• Merely reciting the words "apply it" (or an equivalent) with the judicial exception, or merely including instructions to implement an abstract idea on a computer, or merely using a computer as a tool to perform an abstract idea, as discussed in MPEP § 2106.05(f);
• Adding insignificant extra-solution activity to the judicial exception, as discussed in MPEP § 2106.05(g); and
• Generally linking the use of a judicial exception to a particular technological environment or field of use, as discussed in MPEP § 2106.05(h).
In this instance, “the method of preparing cow ultralong CDR3 antibody display library” or “the method of preparing an ultralong CDR3-knob phage display” comprising steps directed to natural products and/or processes and which “further comprises identifying the CDR3 knob” does not require the artisan to integrate the JEs into a practical application (i.e., fails to further limit the invention in a manner to use in a practical application). For example, the methods of claims 1 and 46 fails to integrate the libraries into a practical application such as prophylaxis or therapy. Furthermore, the methods of claims 48 and 49 fails to recite where dependent claims 48 and 49 steps are applied within independent claim 46, fails to generate new data (i.e., a new sequence or a defined sequence), and fails to integrate the CDR3 knob phage display into a practical application such as prophylaxis or therapy.
[Step 2A (2nd prong): Claims 1, 46, and 48-49: no]
STEP 2B: Do the claims recite a non-conventional arrangement of additional elements that amounts to significantly more than the judicial exception (i.e., Do the additional elements contribute an “inventive concept”?
The second part of the Alice/Mayo test is often referred to as a search for an inventive concept. Alice Corp. Pty. Ltd. v. CLS Bank Int'l, 573 U.S. 208, 217, 110 USPQ2d 1976, 1981 (2014) (citing Mayo Collaborative Servs. v. Prometheus Labs., Inc., 566 U.S. 66, 71-72, 101 USPQ2d 1961, 1966 (2012)).
All elements of claims 1 and 46, are part of one or more identified JEs (as described above) and do not contain additional elements that are sufficient to amount to significantly more than the judicial exception because each step when considered independently and in combination does not amount to more than well-understood, routine, and conventional activity in the development of naïve antibody libraries or immune phage-display libraries, see for example Ponsei, et al., which provides a review of combinatorial antibody library generation (Molecules, 2011, 16, 3675-3700, see abstract and Fig 2).
All elements of claims 48-49 are part of one or more identified JEs (as described above) and do not contain additional elements that are sufficient to amount to significantly more than the judicial exception because each step when considered independently and in combination fails to define where the “further comprising” steps fall within the independent claim reciting a method of preparation of an ultralong CDR3-knob phage display, and furthermore comprise conventional data gathering and post-processing. Furthermore, Stanfield, et al., (Sci Immunol, 2016, 1, 1-21, included in IDS filed 05OCT2023), teaches identifying the CDR3-knob structure from an ultralong HCDR3 (Fig 1 and Fig 4B). Although Stanfield, et al., utilize crystal structure similarities to identify the CDR3-knob structure; the similarities between the beginning and end of the knob structure provide the evidence for identifying the CDR3-knob structure across multiple VH template sequences
[Step 2B: Claims 1, 46, and 48-49: no]
Summary and conclusion regarding claims 1, 46, and 48-49:
In conclusion, the above 101 JE analysis of claims 1, 46, and 48-49, viewed as a whole and considering all elements individually and in combination, no claim recites limitations that transform the claim, finally interpreted as directed to the above-identified JE(s), into patent eligible subject matter.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 47, 49-51, 58, 61, and 63 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 47, recites the phrase "optionally," which 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(h)(II).
Claims 47 and 63 recite the open language “comprising,” which does not exclude additional unrecited elements and also recite the closed language “consisting of,” which does not allow for additional unrecited elements (see MPEP § 2111.03). Therefore, it is unclear how the scope of claims 47 and 63 allow for additional unrecited elements and how they can also exclude additional unrecited elements. One of ordinary skill in the art would not be reasonably apprised of the scope of patent protection sought. For example, it is unclear in regards to claim 47 which recites “…the primers comprise or consist of any of the sequences set forth in SEQ ID NO: 7-11 and 121-130, optionally comprises or consist of any of the sequences set forth in SEQ ID NOL 123, 127, and 128.”, if the patent protection sought is limited to i) the full-length of SEQ ID NOs: 7-11 or 121-130 with or without amino acid residues at either or both ends (i.e., comprising), ii) the full-length of SEQ ID NOs: 7-11 or 121-130 and nothing more or less (i.e., consisting of).
Claim 49 is indefinite because an algorithm to identify the CDR3 knob from the VH sequence comprises identifying the HCDR3 and determining the CDR3 knob sequence does not clearly define the metes and bounds of the claimed invention (i.e., the algorithm requires unknown inputs and results in outputs as related to the CDR3 but does not provide a physical structure). Furthermore, mathematically, claim 49 contains an error, the claim recites “wherein the CDR3 knob is identified from an antibody sequence by an algorithm” and that the CDR3 length is defined as L, the CDR3 knob sequence length is defined as K, the [CDR3 knob] sequence begins at position X + 1 and [the sequence] ends at [position] X + K, and K = L – 2X; wherein in this instance the end position includes the variable that is being calculated and instead should be defined by L – X resulting in the equation K = L – X – X or K = L – 2X.
Claim 49 recites the limitation "The method of claim 48, wherein...comprising: identifying the conserved cysteine in framework 3 …from the first cysteine in framework 3…" does not previously mention the first cysteine in framework 3 and it is therefore unclear whether the first cysteine and the conserved cysteine of framework 3 are the same. Thus, there is insufficient antecedent basis for this limitation in the claim. Claims 50-51 are also rejected since they depend from claim 49, but do not remedy this deficiency.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claims 51, 58, and 61 recite the broad recitations of five amino acids at the N and C-termini, 6 cysteine residues, and 3 disulfide bonds, respectively, and the claims also recite one amino acid at the N or C terminus, 12 cysteine residues, and 5 disulfide bonds, respectively which are the narrower statements of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
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.
Claim 50 is 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. In this instance, claim 50, dependent on claim 49, dependent upon claim 48, which recites “identifying the CDR3 knob from the cow antibody VH [cDNA] template sequences” whereas claim 50 recites, “wherein the antibody sequence is a bovine antibody” which is broader (i.e., includes cattle, bison, buffalo, and yaks) than cow or cattle. 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 Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 46, 62, and 103 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO 2015/010100 (Fabrus, Inc., et al., 22JAN2015, included in IDS filed 05OCT2023), herein referred to as “’100.”
‘100 teaches ultralong CDR3 antibody and fragments thereof (i.e., scFv) and antibody cow knob (i.e., ultralong CDR3 knob) (phage) display libraries for the production of humanized ultralong CDR3 antibodies or ultralong CDR3 knobs (¶00465-00473, ¶00705, Example 2). Specifically, ‘100 teaches multiple methods of production. In one method, humanized antibodies comprising an ultralong CDR3 may be made by using combinatorial libraries to screen for synthetic antibody clones with desired activity or activities. For example, synthetic antibody clones are selected by screening phage libraries containing phage that display various fragments of antibody variable regions {e.g., scFv or Fab) fused to phage coat protein. Such phage libraries may be panned, for example, by affinity chromatography against the desired antigen. Clones expressing antibody fragments capable of binding to the desired antigen may be adsorbed to the antigen and thus separated from the non-binding clones in the library. The binding clones may then be eluted from the antigen, and can be further enriched by additional cycles of antigen adsorption/elution. Any of the humanized antibodies comprising an ultralong CDR3 as disclosed herein may be obtained by designing a suitable antigen screening procedure to select for the phage clone of interest. Variable domains may be displayed functionally on phage, either as single-chain Fv (scFv, also referred to as single-chain antibody (SCA)) fragments, in which VH and VL are covalently linked through a short, flexible peptide (¶00465-00466).
In another method, nucleic acids encoding antibody variable gene segments including VH and VL segments are recovered from cell of interest (i.e., cells from the lymph nodes or the spleen) of a bovine immunized with an antigen (i.e., bovine viral diarrhea virus or BVDV) and may be amplified by recombinant DNA techniques. For example, the desired DNA may be obtained by isolating genomic DNA or mRNA from lymphocytes (i.e., a specific type of WBC, which falls into the broader category of PBMCs) followed by polymerase chain reaction (PCR) with primers matching the 5' and 3' ends of VH and VL genes, thereby making diverse V gene repertoires for expression. The V genes may be amplified from cDNA and genomic DNA, with back primers at the 5' end of the exon encoding the mature V-domain and forward primers based within the J-segment. Library diversity may be enhanced or maximized by using PCR primers targeted to each V-gene family in order to amplify available VH and VL arrangements present in the immune cell nucleic acid sample. VH repertoires may also be made with all the sequence diversity focused in a long H3 loop of a single length (¶00469-00470). Once the templates are amplified, the vectors encoding in this instance the CDR3 knob may be fused to a phage coat protein as described supra.
Per MPEP §2113, even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself (i.e., the patentability of the product does not depend on its method of production). In this instance, the claimed product-by-process is a library of display particles, and the ‘100 prior art teaches ultralong CDR3 anti-BVDV antibody or knob clones (i.e., amplified phagemid particles or a library of display particles) using DNA isolated from an immunized cow, amplifying sequences, constructing vectors for phage display, transforming cells, and collecting the amplified display particles. Given that the ‘100 teachings are drawn to a method of production of ultralong CDR3 antibody and knob clones from a variety of methods, inclusive of phage display technology (i.e., phage display library), while the instant claimed invention can be any phage display library directed to any target antigen, the ‘100 prior art necessarily anticipates the breadth of the instant claimed invention.
Therefore, the prior art anticipates the invention as presently claimed.
Claim 1 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by US 10,562,980 B2 (Smider, et al., 18FEB2020), herein referred to as “’980.”
The ‘980 patent teaches collections, libraries, and arrays of humanized antibodies comprising ultralong CDR3 sequences and that the library or array may be in display format, for example the antibody sequences may be expressed on phage (see col 37, lines 40-43 and col 38, lines 39-41). In example 2, bovine VH regions were amplified from cDNA producing a library of antibody variable region cDNA biased for ultralong CDRs, 132 clones containing unique long CDR HC sequences were selected an co-transfected in parallel with pFUSE expression vector encoding the invariant bovine LC BLV1H12 into cells to generate a small spatially addressed library the antibodies were screened for binding to the antigen target (col 123, lines 1-44)
Therefore, the prior art anticipates the invention as presently claimed.
Claims 46, 48-62, and 103 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO 2021/191424 (UCB Biopharma SRL, et al., 30SEP2021, included in IDS filed 04SEP2024), herein referred to as “’424.”
‘424 teaches that bovine antibody knob domains are capable of binding antigens autonomously, with high affinity, in the absence of the ultralong CDR-H3 stalk region, neighboring CDRs or Fab infrastructure (i.e., ultralong CDR3 knob only antigen binders) and methods of preparing the antibody fragments (Field of invention section and Summary of the invention section). The invention provides a method for generating a phage display library of ultralong CDR-H3 sequences, said method comprising: a) immunizing a bovine with an immunogenic composition (i.e., Complement component 5 or C5), and; b) isolating total RNA from PBMC or secondary lymphoid organ, and; c) amplifying the cDNA sequences of the ultralong CDR-H3, and; d) fusing the sequences obtained in c) to the sequence coding for the pIII protein of a M13 phage within a phagemid vector, and; e) transforming host bacteria with the phagemid vector obtained at step d) in combination with a helper phage co-infection, and; f) culturing the bacteria obtained at step e), and; g) recovering the phages from the culture medium of the bacteria, wherein the immunogenic composition comprises an antigen of interest or immunogenic portions thereof, or DNA encoding the same. In one embodiment, step c) comprises: a) a primary PCR with primers flanking CDR-H3, annealing to the conserved framework 3 and framework 4 of the VH, to amplify all CDR-H3 sequences, and b) a second round of PCR using stalk primers to specifically amplify ultralong sequences from the primary PCR. The sequence of ultralong CDR-H3 can be determined by well-known sequencing methods, and the skilled person will be able to identify the minimal sequence which define a knob domain, based for example on a comparative analysis, with well characterized ultralong CDR-H3 as well as stalk and knob domains thereof, e.g. by alignment with well-known and/or standard nucleic and/or amino acid sequences, and/or based on crystal structure analysis. The invention also provides a phage display library, comprising a plurality of recombinant phages; each of the plurality of recombinant phages comprising an M13-derived expression vector, wherein the M13-derived expression vector comprises a polynucleotide sequence encoding an isolated antibody fragment of the invention fused to the sequence encoding the pIII coat protein of the M13 phage. The invention further provides a method for producing an isolated antibody fragment of the invention (i.e., knob domain of a bovine ultralong CDR-H3 or portion thereof) which binds to an antigen of interest, said method comprising: a) generating a phage display library of isolated antibody fragments of the invention; and, b) enriching the phage display library against the antigen of interest to produce an enriched population of phage which bind the antigen of interest; and, c) sequencing an isolated antibody fragment from the enriched population of phage obtained in step b); and, d) expressing or synthesizing an isolated antibody fragment obtained in step c). The knob domain of a bovine ultralong CDR-H3 or portion thereof is 25 amino acids in length or more, 30 amino acids in length or more, 35 amino acids in length or more, 40 amino acids in length or more, 45 amino acids in length or more, and is up to 55 amino acids in length, comprises at least two, or at least four, or at least six, or at least eight, or at least ten cysteine residues, and comprises at least one, or at least two, or at least three, or at least four, or a at least five disulfide bonds (i.e., 25-70 amino acids in length and a cysteine motif comprising 2-12 cysteine residues able to form 1-6 disulfide bonds).
Therefore, the prior art anticipates the invention as presently claimed.
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.
Claims 47 and 63 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2021/191424 (UCB Biopharma SRL, et al., 30SEP2021, included in IDS filed 04SEP2024), herein referred to as “’424” as applied to claims 46, 48-62, and 103 and as evidenced by Sepulveda, et al., (J Immunol Methods, 2008, 332, 92-102), herein referred to as “Sepulveda.”
The teachings of ‘424 are summarized above.
However, they do not teach: the primer sequences having specific SEQ ID NOs.
Nevertheless, Sepulveda teaches primer design workflow for use in a phage display library, which encompasses investigating the genome and EST sequence databases (i.e., Blast software) to determine the specific coding domain sequences, then the primers were designed to amplify the coding domains in at least one primer combination, containing sequence degeneracy at some positions to maximize amplification efficiency while minimizing the creation of stop codons.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the primer sequences disclosed by ‘424 by designing the specific designated primer sequences using knowledge generally available to one of ordinary skill in the art as evidenced by Sepulveda and furthermore is considered routine practice for the preparation of phage display libraries. One would have been motivated to do so, given the general scientific knowledge of one of ordinary skill in the art that primer design is based on the application and type of library being constructed and in the instance of ‘424 the primer sequences comprised a) primers flanking CDR-H3, annealing to the conserved framework 3 and framework 4 of the VH, to amplify all CDR-H3 sequences, and b) stalk primers to specifically amplify ultralong sequences. There would have been a reasonable expectation of success, given the knowledge that specific primer design workflow is standard for each library (i.e., routine) and the practice of design of primers for a specific application is generally available to one of ordinary skill in the art as evidenced by Sepulveda.
Thus, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time of filing.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAMANTHA L. HOPKINS whose telephone number is (703)756-4666. The examiner can normally be reached Mon-Thurs 6:00 AM to 4:00 PM EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached at (571)272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SAMANTHA LAKE HOPKINS/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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