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 .
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Priority
The instant application, filed 02/22/2024, is a 371 filing of PCT/EP2022/073476, filed 08/23/2022, and claims foreign priority to EP21192859.3, filed 08/24/2021.
Status of Claims/Application
Applicant’s preliminary amendment of 02/22/2024 is acknowledged. Claims 9-15 are amended. Claims 1-15 are currently pending and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 02/22/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Drawings Objection
The drawings are objected to because of the following informalities:
In Figure 7, particularly A, C, and D, and in Figure 11, particularly A, C, and D, the data lines presented in gray scale are close in contrast making it difficult to identify which data line is which with regards to the legend. It is suggested that the contrast be enhanced or the lines be identified by some other means, such as a label.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Interpretation
Instant claims 1 and 5 recite CDRs identified as CDR1 – CDR6. In the instant office action, CDR1, CDR2, and CDR3 are interpreted as being the heavy chain variable region CDR-H1, CDR-H2, and CDR-H3, respectively, and CDR4, CDR5, and CDR6 are interpreted as being the light chain variable region CDR-L1, CDR-L2, and CDR-L3, respectively.
This interpretation is based on the statements made in the specification on page 14, lines 1-4 in which it is stated that CDR-H1, CDR-H2, and CDR-H3 correspond to CDR1, CDR2, CDR3 respectively, and are located in the heavy variable chain of the antibody and that CDR-L1, CDR-L2, and CDR-L3 correspond to CDR4, CDR5, and CDR6 respectively and are located on the light variable chain of the antibody.
Claim Objections
Claim 12 is objected to for the following informality: line 3 of the claim comprises a recitation of “Candida” that is not in italics. It is suggested that, for correctness and for consistency with the rest of the claims, that the word be italicized.
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 14-15 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 14 and 15 recite “Antibody or pharmaceutical composition for use of claim 11” in the preamble. It is unclear if the “for use” recitation in the preambles is extraneous or if applicant is attempting to reference the intended use recited in instant claim 11. If applicant is attempting to reference the “for use” limitation in claim 11, it is unclear if the antibody or pharmaceutical composition in claims 14 and 15 are limited to the antibody/pharmaceutical composition encompassed by claim 11 (antibody of claim 1 or pharmaceutical composition of claim 9), or if the antibody/pharmaceutical composition claimed could be any so long as it is used for the same intended use recited in claim 11.
Appropriate correction is required.
In the instant office action, the claim is interpreted as requiring the antibody or pharmaceutical composition of claim 11.
Claim 14 depends on claim 11 and recites the limitation “wherein preventing, suppressing, or delaying the emergence of a Candida infection in a subject at risk of acquiring a Candida infection in a subject”. There is insufficient antecedent basis for this limitation in the claim rendering the metes and bounds of the claim indefinite. Claim 14 depends on claim 11, which does not recite a method or use of the antibody/pharmaceutical formulation in preventing, suppressing, or delaying emergence of the infection in a subject at risk of acquiring the infection. It is noted that the specification does not provide an explicit definition of “treating” such that the reference is encompassed by the “method of treating” recited in claim 11.
Appropriate correction is required.
Claim 15 recites “the subject at risk of acquiring a Candida infection”. There is insufficient antecedent basis for this limitation in the claim, rendering the metes and bounds of the claim indefinite. Claim 14 depends on claim 11, which does not recite a subject who is at risk of acquiring a Candida infection whom could be being referenced.
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.
Enablement
Claims 3-4 and 7-8 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. Specifically, the specification does not provide evidence that the claimed biological materials are (1) known and readily available to the public; or (2) reproducible from the written description.
The instant claims recite hybridoma cell lines with Accession numbers of DSM ACC 3369 (claims 3-4) or DSM ACC 3368 (claims 7-8).
The disclosure, however, does not provide any additional information regarding the biological deposits recited in the claims and; therefore, does not provide an ordinarily skilled artisan with the ability to make or use the claimed invention.
Specifically, the disclosure does not clearly identify whether the deposit was made under the provisions of the Budapest Treaty. The specification also does not provide the required information regarding the deposit such as: the name and address of the depository; the name and address of the depositor; the date of deposit; and the date of the viability testing. See MPEP 2409 and 37 C.F.R. 1.807.
If the deposit was 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.
Amendment of the specification to disclose details regarding the deposit including 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.
Scope of Enablement
Claims 12-14 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 suppressing or delaying the emergence of a Candida infection in a subject at risk of acquiring a Candida infection, does not reasonably provide enablement for prevention of a Candida infection. 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 commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). The court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is ‘undue,’ not 'experimentation.'" (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all of these factors are considered, a sufficient amount for a prima facie case are discussed below.
The nature of the invention
The instant invention is drawn to the use of an antibody directed against Pra1 of Candida albicans or against Tef1 of Candida albicans and recites that the antibody, or a pharmaceutical composition thereof is used in a method of preventing a Candida infection in a subject at risk of acquiring a Candida infection.
The breadth of the claims
The claims are broad in that they encompass preventing any Candida infection in a subject at risk of acquiring such infection in methods using the claimed antibodies.
The specification does not define “preventing” or “prevention”. In the absence of a limiting definition by the applicants, “prevention” is interpreted as defined according to IIME as provided in Wojtczak, A. (2002) Glossary of Medical Education Terms Medical Teacher 24(4): 357; 1-25. IIME defines “prevention” as promoting health, preserving health, and to restore health when it is impaired, and to minimize suffering and distress (page 16, “Prevention”). IIME states that “primary prevention refers to the protection of health by personal and community wide effects, such as preserving good nutritional status, physical fitness, and emotional well-being, immunizing against infectious diseases, and making the environment safe.” IIME states that “secondary prevention can be defined as the measures available to individuals and populations for the early detection and prompt and effective intervention to correct departures from good health”. IIME further states that tertiary prevention consists of the measures available to reduce or eliminate long-term impairments and disabilities, minimize suffering caused by existing departures from good health”.
Thus, in its broadest reasonable interpretation, the prevention of a Candida infection suggests that the onset of the infection never occurs and the patient’s health is protected and preserved.
The amount or direction provided by the inventor / the existence of working examples
Example 6 of the instant disclosure studies the prophylactic application of mAb in mouse models. In the study, the anti-Pra1 mAb 8C3 or 1E12 or the anti-Tef1 mAb 5E1 or mAb MOPC-21 were injected one day before systemic infection of mice with C. albicans to test for prophylactic activity of the antifungal mAb. The example reports that only mice treated with mAb 5E1 had a lower clinical score than controls. It is also reported that 5E1 treated mice did significantly better than 8C3- or 1E12- treated animals. The results are presented in Figs. 10-11. The example also discloses that fungal burden was high for all mice killed either for humane reasons or at the end of the two-week observation period, as shown in Fig. 12. The example concludes that mAb 5E1 protected mice from C. albicans induced invasive fungal disease.
While the example demonstrates that prophylactic treatment with mAb 5E1 can prolong survival in mice who are systemically infected with C. albicans, the example does not demonstrate the prevention of any Candida infection and, in studies with C. albicans all mice still had fungal burden at the end of the study.
Additionally, neither the examples, nor the instant disclosure, demonstrate a method that could be used by an ordinarily skilled artisan to establish that a subject would have predictably developed a Candida infection without the claimed antibody/pharmaceutical composition treatment in order to establish that the infection was prevented using the claimed methods.
The state of the prior art / the level of predictability in the art
The prior art also does not provide a method that could be used to identify that a subject would have predictably developed a Candida infection without the claimed method in order to establish that such an infection was prevented. Rather, the art suggests that Candida, including C. albicans, are commensal yeast and that infection with Candida is not predictable and depends on numerous potential risk factors.
For instance, Tamo, S.P. B. (2020) Candida Infections: clinical features, diagnosis, and treatment Infect Dis Clin Microbiol 2(2); 91-102 teaches that over 200 species of Candida have been listed, and only around 20 are responsible for human infections. These are generally commensal germs that develop in the skin, inside the body, in the mouth, throat, intestines, vagina, without causing problems. They express their pathogenic power only in the presence of factors favoring the origin of the translation of endogenous commensal to the disease-causing parasite. These factors can be intrinsic or extrinsic to the host. For instance, Tamo teaches that weight, prolonged use of broad-spectrum antibiotic therapy or corticosteroids, etc. and immunosuppression are risk factors (page 91, paragraph 1). Tamo also teaches that inappropriate medical practices, such as misdiagnosis and inadequate medication are responsible for the worsening, spread, and persistence of the infection (page 92, left column, paragraph 1).
Several approaches allowing the efficient diagnosis of candida infections are being used today. Conventional techniques are mainly based on recognizing symptoms, direct collection, and examination of clinical samples, culture and identification of the morphological, biochemical, immunological, or molecular characteristics of the Candida species at the origin of the infection. Candida’s infectious strains differ widely both in their ability to cause infection and their susceptibility antifungal agents (page 92, left column, paragraph 2).
Tamo teaches that C. albicans are commensal yeast from the digestive, genital, and respiratory tract mucosa, and represents more than 75% of yeasts isolated in humans (page 93, Table 1).
Tamo further discuses intrinsic and extrinsic factors favoring candidiasis. The intrinsic factors can be physiological, such as newborn, older adult, overweight, pregnant, etc.; local such as sweating, humidity, maceration, poor hygiene, irritations, etc.; or related to the patient’s pathological condition, such as diabetes, severe malnutrition, or immunosuppression, especially during HIV infection or cancer, etc. Tamo teaches extrinsic factors including prolonged use of corticosteroids or broad-spectrum antibiotic treatments, antiseptics, dentures, intravenous drug use, surgical procedures, organ transplantation, anticancer and cytolytic chemotherapy, radiotherapy, and the use of implanted medical devices such as catheters and probes (paragraph bridging pages 93-94).
Tamo teaches that diagnosis depends on the infection’s location and is based on recognizing symptoms and taking clinical samples, direct examination, culture, and identification of the germs in the sample (page 95, left column, diagnosis).
The teachings of Tamo demonstrate that the art recognized Candida, including C. albicans, as commensal yeast and that a wide range of intrinsic and extrinsic factors favor Candida infection. Teachings which demonstrate unpredictability in identifying which subjects would have gotten a Candida infection without preventative measures such as those claimed.
Difficulties in preventing Candida infection is further discussed in the art.
Eggimann, P., et al (2014) Preventing invasive candida infections. Where could we do better? Journal of Hospital Infection 89; 302-308 further discusses difficulties in the prevention of Candida infections. Eggimann teaches Candida spp. colonization develops in up to 80% of critically ill patients staying more than one week in intensive care, whereas invasive candidiasis is documented in only 5-10% of them. Early diagnosis of invasive candidiasis is difficult; it is generally late in the course of the infection before microbiological evidence is found. This may delay appropriate antifungal treatment and may be in part responsible for its high crude and attributable mortality rates, comparable to those reported for septic shock (paragraph bridging columns, page 302).
Eggimann teaches that antifungal prophylaxis and early empirical treatment of severe candidiasis has improved survival, but may result in overuse of antifungal agents if indiscriminately prescribed to all patients colonized by Candida spp. Indeed, extensive use of antifungals has promoted a shift to Candida spp. with reduced susceptibility. Recent guidelines resulting from expert consensus provided no high-level recommendations about antifungal prophylaxis and empirical antifungal treatment. Despite limited evidence, antifungal prophylaxis and empirical treatment currently rely on the identification of patients with a high documented risk and on the positive predictive value of risk assessment strategies, such as the colonization index, candida score, and predictive rules based
on combinations of risk factors (page 302, right column, paragraph 2 – page 303, left column, paragraph 2). Eggimann concludes suggesting restricting antifungal prophylaxis to surgical patients presenting with
anastomotic leakage after abdominal surgery or reopening of the digestive tract during the same hospitalization to prevent the development of invasive candidiasis (page 307, left column, paragraph 2).
The teachings of Eggimann not only highlight difficulties in predicting Candida infections in patients, but also demonstrate that overuse of preventative treatments can promote shifts to Candida spp. with reduced susceptibility to treatments.
The prior art does not disclose a method that could be used by one of ordinary skill in the art to predictably identify a subject who would acquire a Candida infection without the claimed methods in order to establish that the claimed methods resulted in prevention of infection. Rather, the art suggests that Candida infection is unpredictable and also discourages broad preventative treatment.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure
As discussed in detail above, there is no disclosed or art recognized method through which an ordinarily skilled artisan would be able to determine that a subject would have predictably developed a Candida infection in order to establish that the claimed method acted as a preventative measure. Furthermore, as there is no known or disclosed method that could be used to establish that a Candida infection was prevented using the claimed method as there is no way to predictably know that the subject would have developed a Candida infection without the claimed method. Therefore, in order to implement the invention as claimed, one of ordinary skill in the art would have to participate in undue experimentation to find a method that could be used to determine that a Candida infection was prevented with the real possibility that no such method could be found.
In view of the Wands factors discussed above, a person of ordinary skill in the art would have to engage in undue experimentation to practice the full scope of the claimed invention. As such, the instant claims were determined to not meet the scope of enablement requirement of 35 USC 112(a).
Written Description
Claims 1-2, 5-6, and 9-15 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.
Claim 1 recites an antibody directed against Pra1 of Candida albicans, or an antibody fragment thereof, comprising the recited CDRs 1-6, “wherein any one of the CDR sequences can be altered by substitution, deletion or insertion of 1 or 2 amino acids”.
Claim 5 recites an antibody directed towards Tef1 of Candida albicans, or an antibody fragment thereof, comprising the recited CDRs 1-6, “wherein any one of the CDR sequences can be altered by substitution, deletion or insertion of 1 or 2 amino acids”.
The claims encompass a genus of antibodies in which any one of the CDR sequences can be altered by substitution, deletion, or insertion of 1 or 2 amino acids and claim that the antibodies function in being directed towards Pra1 or Tef1 of Candida albicans.
Claims 11-15 further recite functions of the antibodies in which they are used in methods of treating or preventing, suppressing, or delaying the emergence of a Candida infection.
The instant disclosure, however, does not provide a representative number of species of the claimed genus performing the claimed functions, nor does the disclosure provide a structure function relationship that would allow for the reasonable identification of species within the genus that would perform the claimed functions. See MPEP 2163 II.A.2.a.ii. This is particularly the case in the absence of a full complement of 6 CDRs, specifically 3 from the heavy chain variable region and 3 from the light chain variable region, with 100% sequence identity that is demonstrated as being directed to Pra1 or Tef1 of Candida albicans.
The examples of the instant disclosure demonstrate the generation of mAb targeting immune evasion proteins and their characterization. In example 1, mAbs are generated using the hybridoma technique. Specifically, female BALB/c mice were immunized twice subcutaneously with a four-week interval between injections with 10 μg of purified fungal protein together with the adjuvant TiterMax®. After another three weeks, the mice received an intravenous injection of fungal protein without adjuvant and were sacrificed to obtained splenocytes for mAb isolation (page 10, lines 23-28). Example 2 tested the isolated mAbs for their recognition of linear protein epitopes of C. albicans and identifies clone 8C3 and 1E12 as targeting Pra1 and 5E1 as targeting Tef1 (page 11, Table 1).
Example 7 provides the sequencing of the CDRs of the antibodies of the invention (starting on page 13).
Table 3 provides the CDRs of the anti-Pra1 antibody, 8C3, which are identified as CDR-H1 – CDR-H3 of SEQ ID NOs: 1-3, respectively and CDR-L1 – CDR-L3 of SEQ ID NOs: 4-6, respectively. The heavy and light chain variable regions are identified as SEQ ID NO: 13 and 14, respectively (page 14).
Table 4 provides the CDRs of the anti-TEF1 antibody, 5E1, which are identified as CDR-H1 – CDR-H3 of SEQ ID NOs: 7-9, respectively and CDR-L1 – CDR-L3 of SEQ ID NOs: 10-12, respectively. The heavy and light chain variable regions are identified as SEQ ID NO: 15 and 16, respectively (page 14).
These two antibodies, with 100% sequence identity in the full complement of heavy and light chain CDRs, represent the antibodies that applicant was in possession of at the time of the effective filing date of the claimed invention.
These species are not representative of the full scope of the instantly claimed genus in which any one of the CDR sequences can be altered by substitution, deletion, or insertion of 1 or 2 amino acids. The disclosure also does not provide a sufficient structure function correlation that would allow for the predictable identification of which amino acid sequences in the CDRs could substituted, deleted, or altered while maintaining direction towards Pra1 or Tef1 of Candida albicans and the ability to treat/prevent, suppress or delay Candida infection.
The prior art also does not provide a representative number of species of the claimed genus performing the claimed functions, nor does the prior art provide a structure function correlation that could be used to predictably identify which substitution, deletion, or insertion of 1 or 2 amino acids in the claimed CDRs would retain such function. Rather, the art suggests that antibody structure-function is not predictable.
For instance, Chiu, M.L., et al (2019) Antibody structure and function: The basis for engineering therapeutics Antibodies 8(55); 1-80 teaches that, the antigen-binding site of immunoglobulins is formed by the pairing of the variable domains (VH and VL) of the Fab region. Chiu teaches that each domain contributes three complementarity determining regions (CDRs), specifically, three from the VL and three from the VH, and that the six CDR loops are in proximity to each other resulting from the orientation of the VL and VH regions. Chiu teaches that the configuration of the VL and VH brings the three CDRs of the VL and VH domains together to form the antigen-binding site (page 4, paragraph 2). These teachings of Chiu demonstrate that the interaction between the heavy and light chain variable domains effect the conformation of the binding region of the antibody and therefore the antibody’s ability to bind to its target. Furthermore, the teachings of Chiu point out that the binding site is formed by the combination of the heavy and light chain CDRs (six regions) together. Based on these teachings, an ordinarily skilled artisan would not have been able to predictably identify which species of the instantly claimed genus would be capable of performing the claimed function. This is particularly the case in the absence of a full complement of six heavy and light chain CDRs with 100% identity.
Rabia, L., et al (2018) Understanding and overcoming trade-offs between antibody affinity, specificity, stability, and solubility Biochem Eng. J. 15(137); 365-374 discusses challenges faced during antibody optimization. Rabia discusses the challenges with optimizing antibody properties and states that “natural antibody affinity maturation relies on the introduction of somatic mutations followed by clonal selection of antibody variants with improved affinity. However, not all somatic mutations contribute to antibody affinity… antibodies accumulate some somatic mutations to increase affinity and others to compensate for the destabilizing effects of affinity-enhancing mutations” (page 2, paragraph 4). Rabia further provides an example of researchers who introduced mutations throughout variable frameworks and CDRs and created libraries to sort antibody variants with high antigen binding. In this case an antibody was identified that displayed increased affinity but had a significant reduction in stability (page 3, paragraph 2). Rabia concludes by stating that “a final key area of future work is the development of improved computational methods for predicting mutations in antibody CDRs and frameworks that co-optimize multiple antibody properties” and that “future efforts will also need to improve structural predictions of antibody CDRs – especially the long and highly variable heavy chain CDR3 – to accurately predict CDR mutations that are beneficial to different antibody properties” (page 9, paragraph 4 – page 10 paragraph 2).
Based on the teachings of Rabia, introducing mutations in the antibody structure, particularly in the CDR regions, is not a predictable task and requires experimentation following mutation to ensure that the binding affinity is maintained and a specific, stable antibody is created. Rabia further spoke to the use of libraries and computational methods for predicting and co-optimizing antibody properties and teaches that these methods are not robust enough yet to yield predictable results. These teachings demonstrate that a modification to even one amino acid of an antibody, particularly in the CDRs, would likely result in an antibody that is not suitable for binding or therapeutic use.
It is noted that the specification discloses “The amino acid substitution is preferably a conservative substitution. A “conservative substitution” refers to the substitution of one amino acid by another, wherein the replacement results in a silent alteration. This means that one or more amino acid residues within the CDR sequence of the present invention can be substituted by another amino acid of similar polarity, which acts as a functional equivalent. Substitutes for an amino acid within the sequence may be selected from other members of the class to which the amino acid belongs (i.e. a conservative substitution). For example, one polar amino acid can be substituted by another polar amino acid; one positively or negatively charged amino acid, respectively, can be substituted by another positively or negatively charged amino acid, respectively, et cetera. Classes of amino acids are for example, nonpolar (hydrophobic) amino acids including alanine, leucine, isoleucine, valine, proline, phenylalanine, tryptophan and methionine; polar neutral amino acids including glycine, serine, threonine, cysteine, tyrosine, asparagine, and glutamine; positively charged (basic) amino acids including arginine, lysine and histidine; negatively charged (acidic) amino acids including aspartic acid and glutamic acid.” (page 8, lines 16-30).
This disclosure in the specification, however, does not limit the substitutions to conservative substitutions and, even if it did, the prior art suggests that even conservative substitutions in antibody CDRs is not predictable.
Rojas, G. (2022) Understanding and Modulating Antibody Fine Specificity: Lessons from Combinatorial Biology Antibodies 11(48); 1-22, which was published approximately a year after the effective filing date of the claimed invention, demonstrates that antibody structure and function were still not predictable. For instance, Rojas teaches that epitope mapping results using mutagenesis scanning challenge our notions of conservative and nonconservative amino acid replacements. Several measures have been proposed to evaluate the difference between amino acids, based on physico-chemical distance between them, mutational distance, or evolutionary exchangeability. Tolerability profile to mutations within functional epitopes does not adjust strictly to any of these rules. The critical attributes of each amino acid that should be kept to maintain recognition depend on the particular antibody. For instance, sometimes only tyrosine and phenylalanine residues can be exchanged without effecting antigenicity, pointing to the relevance of their almost-identical aromatic rings, whereas in other epitopes, tyrosine and histidine are exchangeable, reflecting that two different rings can fulfill a similar functional role (page 11, paragraph 1). Teachings which demonstrate that even after the effective filing date of the claimed invention modifications using even conservative substitution were not predictable.
It is not evident from the disclosure, or the prior art, that applicant was in possession of a representative number of species supporting the entire genus of antibodies that are encompassed by the instant the claims. Additionally, there is no disclosed or art recognized structure-function relationship between antibody structure and functionality which would allow for the predictable substitution, deletion, or insertion of 1-2 amino acids in the claimed CDRs while maintaining binding and therapeutic function. Therefore, the instant claims were found to not meet the written description requirement.
It is noted that there is support for variation in the heavy and light chain variable regions of the antibody if the full complement of 6 CDRs were limited to 100% identity.
Claims 2 and 6 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.
Instant claims 2 and 6 depend on claims 1 and 5, respectively, and recite that the antibody can be a human antibody.
The antibodies; however, are not described in the specification in such a way as to reasonably convey to one of ordinary skill in the art that applicant was in possession of the claimed human antibodies at the time of the effective filing date of the claimed invention.
As discussed in detail in the written description rejection above, the examples of the instant specification disclose that the claimed antibodies were generated using mice immunized with purified fungal protein (page 10, example 1). The example states that the mAbs were generated using the hybridoma technique, but does not disclose that this technique involved any genetic modifications required to generate human antibodies. As such, it appears that the claimed CDRs were generated in mice and; therefore, would murine CDRs, not human CDRs.
While the instant disclosure does not provide a limiting definition for “human” antibody, the art recognized definition indicates that, in order to be a human antibody, the sequence must be fully human with no murine sequences. For instance, Harding, F.A., et al (2010) The immunogenicity of humanized and fully human antibodies mAbs 2(3); 256-265 teaches that fully human sequence derived antibodies have no murine sequence, and are largely produced via two sources: phage display technology and transgenic mice. Recently, fully human sequence antibodies isolated from mice carrying genetic modifications such that the murine immunoglobulin genes were disabled and replaced with functional human immunoglobulin loci have been approved for therapeutic use (page 258, right column, paragraph 2). While Harding does disclose methods by which fully human antibodies can be produced by mice, specifically transgenic mice with genetic modifications, it is not evident from the instant disclosure that such mice were used.
Overall, the antibodies of the instant disclosure, and therefore the CDRs of instant claims 1 and 5, were isolated as murine antibodies. The instant disclosure does not appear to provide even a single species of the claimed fully human antibodies nor does the prior art. The disclosure and prior art also do not provide a method through which murine CDRs could be used to form human antibodies comprising no murine sequences. As such, one of ordinary skill in the art would not reasonably recognize that applicant was in possession of the full scope of the claims at the time of the effective filing date and; therefore, the embodiment of claims 2 and 6 in which the antibody is a human antibody does not meet the written description requirement of 35 USC 112(a).
Conclusion
No claims are allowed.
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/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693
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