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 .
Claims Status
Claims 4, 18, 60-61, 76, 82, 89-90, 94, 100-104, 106 and 112 are pending. The indication of allowability set forth in the previous action is withdrawn and prosecution is reopened in view of the following new grounds of rejection for claim 112. Claims 4, 18, 60-61, 76, 82, 89-90, 94, 100-104, 106 and 112 are under examination on the merits.
Election/Restriction
Applicant’s amendment entered 5/6/2026 is acknowledged. .
Applicant elected, without traverse, the following species in the reply filed on 4/16/2024:
A specific VH CDR1 sequence: SEQ ID NO: 18
A specific VH CDR2 sequence: SEQ ID NO: 19
A specific VH CDR3 sequence: SEQ ID NO: 20
A specific VL CDR1 sequence: SEQ ID NO: 23
A specific VL CDR2 sequence: SEQ ID NO: 24
A specific VL CDR3 sequence: SEQ ID NO: 25
One or more specific residues at the VH framework region: G at H15, L at H37, E at H39, T at H40, H at H68, G at H70, H at H72, P at H73, T at H87, A at H88, V at H89, W at H100, E at H101, and K at H105. Upon further consideration, the examiner has withdrawn the election of species requirement for this group G).
One or more specific residues at the VL framework region: S at L2, Y at L3, V at L4, L at L5, T at L6, Q at L7, P at L8, P at L9, S at L10, V at L11, V at L19, K at L45, I at L68, D at L69, N at L80, T at L88. Upon further consideration, the examiner has withdrawn the election of species requirement for this group H).
A specific VH sequence: SEQ ID NO: 8
A specific VL sequence: SEQ ID NO: 10
One or more specific additional therapeutic agents: a second antibody.
The requirement is still deemed proper and is therefore FINAL.
Claims 4, 18, 60-61, 76, 82, 89-90, 94, 100-104, 106 and 112 are under examination on the merits.
Objections and Rejections Withdrawn
The previous objections and rejections are hereby withdrawn due to Applicant’s amendment submitted on 5/6/2026:
Claim objections: claims 18 and 94 for minor informalities.
35 U.S.C. 112(a)—Written Description: claims 3, 82, 89-90, 94 & 100.
35 U.S.C. 112(a)—Scope of Enablement: claims 103 and 106. The previous scope of enablement rejection is withdrawn in favor of the new rejection presented below.
35 U.S.C. 112(b)—Indefiniteness: claims 3, 4, 18, 60-61, 76, 82, 89-90, 94, 100-104 and 106.
35 U.S.C. 112(d)—Improper Dependent: claim 4.
Claim Interpretation
The specification (para. [0092]) indicates that “about” is meant to encompass variations of up to 20% from the specified value.
Regarding the claim limitation “isolated”, specification indicates: “a polypeptide, antibody, polynucleotide, vector, cell, or composition which is "isolated" is a polypeptide, antibody, polynucleotide, vector, cell, or composition which is in a form not found in nature. Isolated polypeptides, antibodies, polynucleotides, vectors, cell or compositions include those which have been purified to a degree that they are no longer in a form in which they are found in nature.” (para. [0070]).
Claim 82 includes the limitation “the antibody is a [..] chimeric antibody” on line 3. However, PGT121 appears to be from a human patient and has human CDRs, and thus can never be a humanized antibody. The chimeric antibody in claim 82 would therefore have VH and VLs that are human.
New Claim Objections
The claims are objected to because they include reference characters which are not enclosed within parentheses. Specifically, claims 60 and 112 use the format “a.”, etc., rather than “a)”, as is required.
Reference characters corresponding to elements recited in the detailed description of the drawings and used in conjunction with the recitation of the same element or group of elements in the claims should be enclosed within parentheses so as to avoid confusion with other numbers or characters which may appear in the claims. See MPEP § 608.01(m).
Claims 4 and 61 are objected to because of the following informalities: claim 4, line 8 recites “a) the VH CDR1, VH CDR2, and VH CDR3 comprises”, but should instead state “a) the VH CDR1, VH CDR2, and VH CDR3 comprise”. Claim 4 has a similar issue on line 16, as does claim 61 on lines 2 and 3. Appropriate correction is required.
Claim 4 is objected to because of the following informalities: claim 4, line 5 recites “complementary determining region”, but should instead state “complementarity determining region”. Appropriate correction is required.
Claim 60 is objected to because of the following informalities: claim 60 recites “u. a VH comprising the amino acid sequence of SEQ ID NO: 112-126 and a VL comprising the amino acid sequence of SEQ ID NO: 127-139”. However, each of SEQ ID NOs: 112-126 and 127-139 is a complete VH or VL sequence, so it is obvious that Applicant intends to the VH to be one of the recited sequences and VL to be one of the other respective recited sequences. The examiner is interpreting part u. to mean: selected from the groups consisting of: SEQ ID NOs: 112-126, and SEQ ID NOs: 127-139, respectively. Appropriate correction is required.
Claim 100 is objected to because of the following informalities: claim 100, lines 2-3 recites “a nucleotide encoding”, but should instead state “an isolated polynucleotide encoding.” Appropriate correction is required.
New Claim Rejections
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 4, 18, 60, 61, 82, 89, 90, 94, and 100 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.
With respect to claim 4’s language “an antibody”, the specification indicates that “antibody” means an immunoglobulin molecule (or group of immunoglobulin molecules) that recognizes and specifically binds to a target through at least one antigen recognition site within the variable region of the immunoglobulin molecule (para. [0045]). This definition reads on polyclonal antibodies, which render the claim indefinite because it is not clear where the 6 CDRs are located. There are multiple structural interpretations, such that the full scope of the claims is unclear. The CDRs could be on any combination of different molecules in a polyclonal antibody. ”A claim may be rendered indefinite when a limitation of the claim is defined by reference to an object and the relationship between the limitation and the object is not sufficiently defined. That is, where the elements of a claim have two or more plausible constructions such that the examiner cannot readily ascertain positional relationship of the elements, the claim may be rendered indefinite.” See, e.g., Ex parte Miyazaki, 89 USPQ2d 1207 (Bd. Pat. App. & Inter. 2008). MPEP §2173.05(b). Claims 18, 60, 61, 82, 89, 90, 94, and 100 depend on claim 4 but do not resolve this lack of clarity, and thus are also rejected.
The examiner suggests amending “an antibody” to be “a monoclonal antibody”, throughout the claims, to avoid this enablement issue.
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.
Scope of Enablement
Claims 4, 18, 60, 61, 76, 82, 89, 90, 94, 100-104, 106, and 112 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for monoclonal anti-HIV gp120 antibodies, wherein the antibody comprises a complete set of CDRs defined by sequence and shown to bind HIV gp120 together, or monoclonal neutralizing antibodies against HIV gp120 that have been shown to neutralize HIV, isolated host cells comprising polynucleotides encoding a monoclonal anti-HIV gp120 antibody, or a method of producing an engineered variant of PGT121 by substituting an amino acid residue of the PGT121 VH or VL not in a CDR region, does not reasonably provide enablement for similar antibodies containing an incomplete set of CDRs or not shown to bind HIV gp120 together, such as antibodies that are claimed using six CDRs from different parental antibodies or wherein the antibody is claimed using heavy chain and light chain CDR libraries, neutralizing antibodies against HIV gp120 that have not been shown to neutralize HIV, unisolated host cells comprising polynucleotides encoding an anti-HIV gp120 antibody, anti-HIV gp120 antibodies that are not monoclonal, or a method of producing an engineered variant of PGT121 by substituting an amino acid residue of the PGT121 VH or VL in a CDR region. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or use the invention commensurate in scope with these claims.
The breadth of the claims is found in claims 4 and 76.
The nature of the invention is an antibody or antigen binding fragment thereof capable of binding HIV gp120, wherein the antibody or antigen binding fragment thereof comprises a heavy chain variable domain and a light chain variable domain, wherein the VH comprises a VH CDR1, VH CDR2, VH CDR3, and the VL comprises a VL CDR1, VL CDR2, and VL CDR3, wherein the VH CDR1, VH CDR2, and VH CDR3, each CDR with particular sequences (claim 4). Additionally, claim 18 allows for sequence variation in the VH and VL of up to 10% (claim 18). Claim 112 is a method for producing an engineered variant of PGT121 comprising substituting one or more particular amino acid residues of the PGT121 VH or VL.
The level of skill of one skilled in this art is high.
The specification demonstrates that a number of the claimed antibodies (ePGT121.15.H1.L1, ePGT121.15.H2.L1, and ePGT121.15.H6.L1) exhibit increased neutralization breadth of HIV strains relative to another antibody, PGT121 (Table 6), and that a number of other variants (n=8, including those three mentioned above), neutralize a number of HIV strains (Fig. 6A). The specification indicates all 6 CDRs for these antibodies (Table 1-3). These teachings do not enable the full breadth of the claims because an antibody lacking any of the 6 parental CDRs would not predictably bind antigen.
The state of the prior art is such that it is well established in the art that the formation of an intact antigen-binding site of antibodies generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs or hypervariable regions, which provide the majority of the contact residues for the binding of the antibody to its target epitope (Paul, Fundamental Immunology, 3rd Edition, 1993, pp. 292-295, under the heading “Fv Structure and Diversity in Three Dimensions”). The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity, which is characteristic of the immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites (Paul, page 293, first column, lines 3-8 and line 31 to column 2, line 9 and lines 27-30).
In the case of antibodies, it is especially important to disclose which residues are permissive to mutation. Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al. (Proceedings of the National Academy of Sciences USA, Vol., 79, Pg. 1979-1983, 1982). Rudikoff et al. teach that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function.
Additionally, Bendig M. M. (Methods: A Companion to Methods in Enzymology, 1995; 8:83-93) reviews that the general strategy for “humanizing” antibodies involves the substitution of all six CDRs from a rodent antibody that binds an antigen of interest, and that all six CDRs are involved in antigen binding (see entire document, but especially Figures 1-3). It is noted that Bendig used Kabat CDRs in their humanization process (Pg. 86, Column 2, Paragraph, second). Similarly, the skilled artisan recognized a “chimeric” antibody to be an antibody in which both the heavy chain variable region (which comprises the three heavy chain CDRs) and the light chain variable region (which comprises the three light chain CDRs) of a rodent antibody are recombined with constant region sequences from a human antibody of a desired isotype (see entire document, but especially Figures 1-3).
Not knowing, absent further experimentation, which modifications function and which do not, when, as set forth above, even a single change of an encoded amino acid can unpredictably affect antibody structure and function, leads to one having no predictability or expectation of success for the function of any given antibody modification. Such random experimentation to identify at a later time what structure or fragment or modification is or is not functional and is embraced by Applicant’s claims is undue experimentation. This affects all claims that can mutate any CDR by reciting percent identity, for example claim 18.
Moreover, claims not containing elements critical or essential to the practice of the invention, such as antibodies or antibody fragments not having all of the relevant functional complementarity determining regions (CDRs) in the proper site on an appropriate antibody heavy or light chain framework, are not enabled by the disclosure. See In re Mayhew, 527 F.2d 1229, 188 USPQ 356 (CCPA 1976).
Note that an enabling disclosure for the preparation and use of only a few analogs of a product does not enable all possible analogs where the characteristics of the analogs are unpredictable. See Amgen Inc. v. Chugai Pharmaceutical Co. Ltd. (18 USPQ 2d 1027 (CAFC 1991)).
Thus, the state of the art recognized that it would be highly unpredictable that a specific antibody binding domain comprising less than all six parental CDRs would have antigen binding function. The minimal structure which the skilled artisan would consider predictive of the function of binding the antigen of an antibody includes six CDRs (three from the heavy chain variable region and three from the light chain variable region) in the context of framework sequences which maintain their correct spatial orientation and have the requisite binding function. One of skill in the art would neither expect nor predict the appropriate functioning of the antibodies as broadly as currently claimed.
With respect to claim 4’s language “an antibody”, the specification indicates that “antibody” means an immunoglobulin molecule (or group of immunoglobulin molecules) that recognizes and specifically binds to a target through at least one antigen recognition site within the variable region of the immunoglobulin molecule (para. [0045]). This definition reads on polyclonal antibodies, which are not enabled by the instant specification. The examiner suggests amending “an antibody” to be “A monoclonal antibody”, throughout the claims, to avoid this enablement issue. This pertains to claim 4’s dependent claims 18, 60, 61, 82, 89, 90, and 100.
With respect to claim 4’s language “wherein the antibody or antigen binding fragment thereof” comprises a VH and VL, “wherein the VH comprises a VH CDR1, VH CDR2, and VH CDR3, and the VL comprises a VL CDR1, VL CDR2, and VL CDR3”, the examiner is interpreting this claim to mean that only the antibody must have all 6 CDRs, but the fragment does not, it could have 3 CDRs from either the VH or VL. Because all 6 CDRs are required for enablement, yet this language means the fragment could only have 3 CDRs, it is not enabled to the full scope of the claims. To resolve this issue, Applicant could amend to say “wherein the antibody or antigen binding fragment thereof each comprises” prior to limitations about the variable domains or CDRs.
The concept of compensatory mutation is well known in this art. That is to say that as antibodies undergo somatic hypermutation, they receive mutations that destabilize their interaction with antigen as well as strengthen said interaction. Destabilizing mutations are compensated by compensatory mutations, yielding an antibody with equal or greater binding affinity for antigen. Bonsignori (Cell, Vol. 165, Pg. 449-463, 2016) teaches that compensatory mutations can occur in CDR regions (Pg. 459, entire page). This again illustrates that one CDR that functions in one parental antibody, may not be able to play the same role in a second antibody with five other CDRs with which it did not evolve. Thus, clearly, barring evidence to the contrary, no one of ordinary skill in this art would assume that mixed and matched CDRs, even from functional anti-gp120 antibodies, would necessarily work in concert to bind antigen. There was no selection for them to work together to function.
Additionally, it is well-known in this art that functional CDRs, when mixed and matched may not work together. The six CDRs of antibodies like those of the instant claims need to complement one another. Meaning each can add to the binding of the antigen in particular ways. In vivo antibody CDRs are selected as a set and so are optimized to function together. However, removing a CDR that was selected to work in its antibody position and replacing it with what one believes to be a functionally equivalent CDR in the same position from a separate set of six CDRs evolved together in a different cell would not be expected to predictably yield a functional set of six CDRs and thus a functional antibody. This well-known concept led to the creation of the CDR implantation method, an improvement over CDR-walking technology, as taught by Soderlind (Immunotechnology, Vol. 4, Pg. 279-285, 1999). They teach that in CDR-walking, CDR sequences are optimized one at a time and then fixed before the procedure moves to optimize the next CDR. However, these chosen/fixed CDRs might not contain optimal sequences in combination with one or several other CDR sequences (Pg. 284, Column 2). They state that it is important to utilize a set of different CDR sequence combinations in a library format to select the best combinations (evolve them all together). Thus, an HCDR1 from a parental antibody may not work well or at all in the same position of a child antibody after several rounds of in vitro evolution. Furthermore, Soderlind specifically points out that screening is required to test different antibody combinations. Screening an antibody library with defined CDRs that are not known to function together placed in frameworks undefined would not be expected to yield functional antibodies, let alone identify all 90 antibodies of the instant claims as having sufficient binding affinity to HIV gp120. One of ordinary skill in this art would not have any expectation of succeeding with all 90 antibodies for the reasons discussed with respect to the work of Soderlind above. Also, they would not find the specification encouraging. The specification, Tables 1-2 and 6 provides no more than 34 variable heavy chain sequences, 19 variable light chain sequences, and 8 functional antibody variants shown to neutralize a number of HIV strains (Fig. 6A). Thus, there is a huge discrepancy between the enablement of the disclosure, in the functional sets of six CDRs taught, and the breadth of the instantly claimed antibodies or antigen binding fragments thereof.
There are 90 possible antibodies in claim 4. The specification does not appear to show validation of all 90 of these resulting from VH and VL from claim 4. Though Applicant made and validated some variants, the claims are essentially taking every CDR from every variant and reciting it in each combination. However, as discussed above, if each variant antibody, and in particular the combination of CDRs, was not made and tested to be functional, the claimed library is not enabled. When dealing with clonal libraries of antibodies, as here, when you make a mutation in the clone, functional validation is necessary. However, the function of the antibody becomes unpredictable when CDRs from different clones are mixed, because when CDR mutations occur naturally, there is no indication of what, if any, compensatory mutation is present. So when a mutation decreases CDR binding, and is compensated for by a second mutation, it is unclear which mutation is decreasing binding versus compensating for binding. Importantly, the compensatory mutation might not be in the same CDR that mutated to possess a negative mutation. Accordingly, to be enabled, it is critical have 6 full-length, validated CDRs for a functional antibody like those claimed. Because the claims are drawn to antibodies encompassing mutated CDRs, the art is very clear that mutation is unpredictable, even if the antibodies are clonal (from same parent), because of the way compensatory mutations work—it is still not predictable to mix and match.
Regarding claim 60, which requires an antibody or antigen binding fragment of claim 4, wherein the antibody comprises particular VH and VL amino acid sequences, to be enabled, each clone must be made and validated to bind HIV gp120. When one looks to the specification, it does not appear that each of the claimed sequences was made. For example, the specification (Table 1), 34 variable heavy chain clone sequences, and 19 variable light chain clone sequences are disclosed. Additionally, part u. of claim 60 recites “a VH comprising the amino acid sequence of SEQ ID NO: 112-126 and a VL comprising the amino acid sequence of SEQ ID NO: 127-139, meaning that any of the VHs can be paired with any of the VLs. The specification does not appear to indicate that antibodies encompassing every combination of these VH+VL were made and tested.
Regarding claim 112, it encompasses a method of producing an engineered variant of PGT121 comprising substituting one or more particular amino acid residues of the PGT121 VH or VL. However, the mutations appear to encompass mutations in the CDRs of PGT121, which is not enabled.
In view of the lack of the predictability of the art to which the invention pertains as evidenced by Paul and Bendig, the lack of guidance and direction provided by applicants, and the absence of working examples, undue experimentation would be required to make and use functional antibodies with binding domains having mutated or fewer than all six CDRs with a reasonable expectation of success, absent a specific and detailed description in applicant’s specification of how to effectively practice this and absent working examples providing evidence which is reasonably predictive that the claimed antibodies are functional, commensurate in scope with the claimed invention.
Regarding claims 76, 101-104, and 106, Applicant broadly claims an antibody or antigen binding fragment thereof capable of binding HIV gp120, wherein the antibody or antigen binding fragment thereof comprises a VH and VL that comprise the amino acid sequences of SEQ ID NO: 8 and 10, respectively, which is used in a method of neutralizing an HIV virus (claim 101), reducing the likelihood of HIV infection in a subject exposed to HIV (claim 102), treating HIV infection (claims 103 and 106), or reducing HIV-1 viral load (claim 104). It is understood that in order to neutralize HIV virus, reduce the likelihood of HIV infection, treat HIV infection, or reduce HIV-1 viral load, the antibody would need to be neutralizing against HIV. When one looks to the specification for support that the claimed antibody can neutralize HIV, Table 6 indicates that ePGT121.15.H6.L1, which appears to have the VH of SEQ ID NO: 8 and VL of SEQ ID NO: 10, does not neutralize all strains of HIV tested, so the claimed antibody does not appear to be enabled against neutralizing a generic HIV infection since it only neutralized 77% of tested strains, not to mention other strains not included in the testing. Along these lines, it is not apparent how tightly this particular antibody of claim 76 and used in the methods of 101-104 and 106 binds to HIV gp120, for example.
With respect to claim 82, which encompasses “b) [..] an isolated VH domain” it is not enabled because it requires less than a full set of 6 CDRs, which are necessary for enablement, see the work of Paul above.
Regarding claims 94 and 100, Applicant broadly claims a host cell comprising a polynucleotide encoding the antibody or antigen binding fragment thereof of claim 4 (claim 94), or a method of producing the antibody or antigen binding fragment thereof of claim 4, comprising culturing the host cell (claim 100). The claims read on a cell within a transgenic animal or a transgene therein given that the term "isolated" is not denoted in describing the host cell, nucleic acid, or vector.
With respect to the unisolated host cells and transgenes as “polynucleotide“ of the instant claims discussed above, the state of the art at the time of filing was such that one of skill could not predict the phenotype of transgenics. The art of transgenic animals has for many years stated that the unpredictability lies, in part, with the site or sites of transgene integration into the target genome and that "the position effect" as well as unidentified control elements are recognized to cause aberrant expression of a transgene (Wall et al., Theriogenology, Vol. 45, Pg. 57-68, 1996).
The elements of the particular construct used to make transgenic animals are also held to be critical, and they must be designed case by case without general rules to obtain good expression of a transgene; e.g., specific promoters, presence or absence of introns, etc. (Houdebine et al., Journal of Biotechnology, Vol. 34, Pg. 269- 287, 1994). Furthermore, transgenic animals are regarded to have within their cells, cellular mechanisms that prevent expression of the transgene, such as methylation or deletion from the genome (Kappell et al., Current Opinions in Biotechnology, Vol. 3, Pg. 548-553, 1992). Houdebine (Comparative Immunology, Microbiology, and Infectious Diseases, Vol. 32, Pg. 107-121, 2009) teaches progress has been made in the field of transgenic animals for production of foreign proteins (Abstract); however, constructing an efficient expression vector to produce a therapeutic protein is not a standard operation (Pg. 116, Paragraph, second). Therefore, undue experimentation is required to make and use a transgene and transgenic animal to produce the antibody and antibody fragments of the instant claims.
Examples in the literature aptly demonstrate that even closely related species carrying the same transgene construct can exhibit widely varying phenotypes. Mullins (1993, Hypertension, Vol. 22, No. 4, pp. 630-633) states that not all animals express a transgene sufficiently to provide a model for a disease as the integration of a transgene into different species of animal has been reported to give divergent phenotypes. For example, several animal models of human diseases have relied on transgenic rats when the development of mouse models was not feasible. Mullins (1990, Nature, Vol. 344, 541-544) produced outbred Sprague-Dawley x WKY rats with hypertension caused by expression of a mouse Ren-2 renin transgene. Hammer (1990, Cell, Vol. 63, 1099- 1112) describes spontaneous inflammatory disease in inbred Fischer and Lewis rats expressing human class I major histocompatibility allele HLA-B27 and human 02- microglobulin transgenes. Both investigations were preceded by the failure to develop human disease-like symptoms in transgenic mice expressing the same transgenes that successfully caused the desired symptoms in transgenic rats (Mullins, 1989, EMBO J., Vol. 8, pages 4065-4072). Thus, the use of nonmurine species for transgenesis will continue to reflect the suitability of a particular species for the specific questions being addressed, bearing in mind that a given construct may react very differently from one species to another.
The examiner notes here, in addition to these issues, even assuming arguendo PHOSITA could make a host organism with functional transgene that encodes the instantly antibody, there is no predictability that the host will survive its expression. The transgene depends on the host for function and harm to the host, including death, renders the transgene nonfunctional and thus not enabled.
The art is well-aware of side effects caused by therapeutic antibodies such as the one instantly recited. In a transgenic cell or animal that expresses the same, the antibody will exert any possible side effect it can. It is not administered but chronically present and so such side effects are chronic and potentially more serious than any from an administered antibody. Hansel (Nature Reviews Drug Discovery, Vol. 9, Pg. 325-337, 2010) teaches in their table 1 on page 328 numerous exemplary side effects from licensed monoclonal antibodies to include: increased bleeding risk, infection, heart failure, cancer, thyroid disorder, autoimmune reactions, and cytokine release syndrome (CRS) to name only a few. One or more such effects, or similar, may occur with the antibody instantly recited when administered and indeed be exacerbated by chronic exposure due to internal expression. The instantly encoded antibody may very well target related or unrelated proteins in the transgenic host, leading to such side effects. For all these reasons, previously raised and new, transgenes are not enabled.
At the time of filing, the phenotype of a transgene and transgenic cell contained within any animal was unpredictable. The claims as written, encompassing a transgene and cell in a transgenic animal, are not adequately described in the specification as to prevent excessive experimentation by the public to generate and use the invention. Applicants can obviate the instant rejection by amending the claims to recite the term "isolated" before the recitation, "host cell" or amending to specify that they are not in a transgenic animal. Applicant may consider using purified in such claims if description is appropriate for such a term and it is not redefined away from standard meaning. Method claims using these products should also carry the appropriate adjectives above.
In view of the lack of the predictability of the art to which the invention pertains as evidenced by the art above, the lack of guidance and direction provided by Applicant, and the absence of working examples, undue experimentation would be required to make and use functional antibodies comprising fewer than all six parental CDRs or comprising mutated versions thereof, or polynucleotides that produce said antibodies, with a reasonable expectation of success, absent a specific and detailed description in Applicant’s specification of how to effectively practice this and absent working examples providing evidence which is reasonably predictive that the claimed antibodies are functional, commensurate in scope with the claimed invention. The same can be said for the transgenes and transgenic animals encompassed by the instant claims. Thus, the claims are rejected here.
Enablement – Deposit
Claim 112 is rejected under 35 U.S.C. § 112 (pre-AIA ), first paragraph or 35 U.S.C. 112(a), because the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention, because the specification does not provide evidence that the claimed biological materials are (1) known and readily available to the public; (2) reproducible from the written description.
It is unclear if a cell line which produces an PGT121 or an engineered variant thereof is known and publicly available, or can be reproducibly isolated without undue experimentation. Therefore, a suitable deposit for patent purposes is suggested. Without a publicly available deposit of the above cell line, one of ordinary skill in the art could not be assured of the ability to practice the invention as claimed. Exact replication of: (1) the claimed cell line; (2) a cell line which produces the chemically and functionally distinct antibody claimed; and/or (3) the claimed antibody's amino acid or nucleic acid sequence is an unpredictable event.
Harris (Biotechnology, Vol. 11, Pg. 1293-1297, 1993) describes heterogeneity in the heavy chain of a recombinant antibody directed against human epidermal growth factor receptor-2 (Abstract). During transfection of antibody heavy and light chain genes into Chinese hamster ovary cells, the mutation Y376Q developed. When the cell line was propagated, 10% of subclones produced high levels of this variant while 90% produced antibody with the expected heavy and light chain sequences (Abstract). Therefore, alterations to antibody amino acid sequence do occur in processes of antibody reproduction without a hybridoma and can affect the reproducibility of a specific antibody species. Qin (US2022/0281997, published 09/08/2022) teaches that a monoclonal antibody is obtained from a population of substantially homogeneous antibodies wherein each is the same and/or binds the same epitope and also includes the antibody containing naturally occurring mutations that occurred during monoclonal antibody production (0069). Such variants are generally present in small amounts (0069). However, this makes clear that an antibody clone such as PGT121, or an engineered variant thereof, need not contain only the VH and VL sequences provided by Applicant in the specification, but as a clone, can contain other sequences not provided. Thus, for practice of making and using the full scope of the claim, deposit of the PGT121 antibody is required.
Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al (Proc. Natl. Acad. Sci. USA, 79(6):1979-1983, March 1982). Rudikoff et al. teach that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function. Colman P. M. (Research in Immunology, 145:33-36, 1994) teaches that even a very conservative substitution may abolish binding or may have very little effect on the binding affinity (see pg. 35, top of left column and pg. 33, right column). Taken together, it would require undue experimentation to reproduce the claimed antibody species PGT121, or engineered variants thereof. Deposit of the hybridoma would satisfy the enablement requirements of 35 U.S.C. § 112, first paragraph. See, 37 C.F.R. 1.801-1.809.
If the deposit is made under the provisions of the Budapest Treaty, filing of an affidavit or declaration by applicant or assignees or a statement by an attorney of record who has authority and control over the conditions of deposit over his or her signature and registration number stating that the deposit has been accepted by an International Depository Authority under the provisions of the Budapest Treaty and that all restrictions upon public access to the deposited material will be irrevocably removed upon the grant of a patent on this application. This requirement is necessary when deposits are made under the provisions of the Budapest Treaty as the Treaty leaves this specific matter to the discretion of each State.
If the deposit is not made under the provisions of the Budapest Treaty, then in order to certify that the deposits comply with the criteria set forth in 37 CFR 1.801-1.809 regarding availability and permanency of deposits, assurance of compliance is required. Such assurance may be in the form of an affidavit or declaration by applicants or assignees or in the form of a statement by an attorney of record who has the authority and control over the conditions of deposit over his or her signature and registration number averring:
(a) during the pendency of this application, access to the deposits will be afforded to the Commissioner upon request:
(b) all restrictions upon the availability to the public of the deposited biological material will be irrevocably removed upon the granting of a patent on this application:
(c) the deposits will be maintained in a public depository for a period of at least thirty years from the date of deposit or for the enforceable life of the patent of or for a period of five years after the date of the most recent request for the furnishing of a sample of the deposited biological material, whichever is longest; and
(d) the deposits will be replaced if they should become nonviable or non-replicable.
In the instant case, the specification fails to state that a hybridoma that produces PGT121 or an engineered variant thereof was deposited. Further, it is not clear that a deposit was made under the terms of the Budapest Treaty, nor is there available a viability statement, i.e. one certifying that the deposit was viable at the time of the deposit or a certificate verifying such from the depository.
Amendment of the specification to recite the date of deposit and the complete name and address of the depository is required. As an additional means for completing the record, applicant may submit a copy of the contract with the depository for deposit and maintenance of each deposit.
If a deposit is made after the effective filing date of the application for patent in the United States, a verified statement is required from a person in a position to corroborate that the biological material described in the specification as filed is the same as that deposited in the depository, stating that the deposited material is identical to the biological material described in the specification and was in the applicant's possession at the time the application was filed.
Applicant's attention is directed to In re Lundak, 773 F.2d. 1216, 227 USPQ 90 (CAFC 1985) and 37 CFR 1.801-1.809 for further information concerning deposit practice.
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.
Claim 82 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. Claim 82 recites “wherein a) the antibody is a recombinant antibody [..]”. However, the antibodies of claim 4, upon which claim 82 depends, appear to have been recombinantly produced. Accordingly, this aspect of claim 82 fails to further limit claim 4. 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 – Improper Markush Grouping
Claims 4, 18, 60, 82, 89, 90, 94, 100, and 112 are rejected on the judicially-created basis that they contain an improper Markush grouping of alternatives.
See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984).
The improper Markush grouping includes species of the claimed invention that do not share both a substantial structural feature and a common use that flows from the substantial structural feature. The members of the improper Markush grouping do not share a substantial structural feature and a common use that flows from the substantial structural feature for the following reasons:
MPEP 803.02 provides guidance on the analysis of a proper Markush group. Members of a proper Markush group are disclosed in the specification to possess at least one property in common which is mainly responsible for their function in the claimed relationship, and it is clear from their very nature or from the prior art that all of them possess this property. The MPEP further provides that in the members of a proper Markush group there should be (1) a common utility, and (2) a substantial structural feature essential to that utility.
In the instant case, claims 4, 18, and 60 include the group of antibody or antigen binding fragment thereof capable of binding HIV gp120, and claim 112 includes a method of producing an engineered variant of PGT121, but they do not appear to share a substantial structural feature. Since the instant claims contain Markush groups with members of antibodies or antigen-binding fragments that possess differing sequences lacking shared, discernable, discrete domains associated with the claimed function of antibody activity (i.e., binding HIV gp120), the claims contain an improper Markush group and are rejected here.
It is not even clear that the antibodies share the same function; even if they all bound spike protein, and shared that function, there is no maintained CDR set required to confer that function amongst them all. As demonstrated by the specification’s Tables 1-2 and the application’s Sequence Listing, these antibodies do not share CDRs, and to be a proper Markush group, the antibodies would need to share the entire set of CDRs. Thus, the antibodies represent improper Markush groups. Accordingly, a common use cannot flow from a shared substantial structural feature in these claims because said structural feature would be the CDR set. Since the instant claims contain Markush groups with members of antibodies that possess differing CDR sequences lacking shared, discernable, discrete domains associated with the claimed function of binding HIV gp120, the claims contain an improper Markush group and are rejected here. For claim 112, some of the claimed mutations are in the CDR regions of the antibody, and thus a common use cannot flow from a shared substantial structural feature in the claim. Claims 18, 60, 82, 89, 90, 94, and 100 depend from claim 4 but do not introduce a proper Markush group for these issues.
In response to this rejection, Applicant should either amend the claim(s) to recite only individual species or grouping of species that share a substantial structural feature as well as a common use that flows from the substantial structural feature, or present a sufficient showing that the species recited in the alternative of the claims(s) in fact share a substantial structural feature as well as a common use that flows from the substantial structural feature. This is a rejection on the merits and may be appealed to the Board of Patent Appeals and Interferences in accordance with 35 U.S.C. §134 and 37 CFR 41.31(a)(1).
Claim Rejections - 35 USC § 103
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 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.
Claim 112 is rejected under 35 U.S.C. 103 as being unpatentable over Ewert, et al. (Methods. 2004 Oct;34(2):184-99. doi: 10.1016/j.ymeth.2004.04.007. PMID: 15312672).
The Prior Art
Ewert teaches stability improvement of antibodies for extracellular and intracellular applications (Title). Ewert further discloses an alignment of the human germline family consensus sequences, (Fig. 2), which shows a valine at position H2, glycine at position H15, serine at position H31, leucine at position H45, alanine at position H60, threonine at position H68, isoleucine at position H69, serine at position H82B, valine at position H82C, alanine at position H88, or valine at position H89, of the VH3 family, and teaches that in the case of the VH domains, they found that the hVH3 germline family consensus domain was the most stable (pp. 185-188, bridging para.). Ewert also teaches that VH families 1 and 5 exhibit intermediate stabilities and little or no tendency to aggregate, whereas exhibited low cooperativity during denaturant-induced unfolding, lower production yields, and higher aggregation tendencies VH families 2, 4, and 6 (p. 188, col. 1, para. 1). However, Ewert does not teach the antibody PGT121 specifically.
It would have been obvious to one of ordinary skill in the art to modify any antibody, such as PGT121, to make a VH with more sequence similarity to the more stable family of human VH, VH3. Therefore, mutations including: valine at position H2, glycine at position H15, serine at position H31, leucine at position H45, alanine at position H60, threonine at position H68, isoleucine at position H69, serine at position H82B, valine at position H82C, alanine at position H88, or valine at position H89, as required by claim 112 were prima facie obvious, because they are associated with improved antibody stability. Additionally, it would have been obvious to introduce any mutations present in the VH families 1 or 5, as they exhibit intermediate stabilities and little or no tendency to aggregate. One of ordinary skill in the art would have been motivated to improve antibody stability. There would be a reasonable expectation of success because VH3 exhibits the highest antibody stability. Therefore, claim 112 was prima facie obvious before the priority date of the instant invention.
Conclusion
No claim is allowed.
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/JEFFREY MARK SIFFORD/Examiner, Art Unit 1671 /Michael Allen/Supervisory Patent Examiner, Art Unit 1671
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