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 .
1. Formal Matters
A. In the response submitted 12/1/25, Applicants elected species are acknowledged. However, upon further examination, all species have been examined.
B. Claims 1-18 are pending and are the subject of this Office Action.
2. Specification
A. When a sequence is presented in a drawing, regardless of the format or the manner of presentation of that sequence in the drawing, the sequence must still be included in the Sequence Listing and a sequence identifier ("SEQ ID NO:X") must be used either in the drawing or in the Brief Description of the Drawings. See MPEP § 2422.02. In the instant application, a sequence identifier must be used for the sequences appearing in Figure 1.
B. It is noted that SEQ ID NO:65, which appears in paragraph [124] of the specification, also appears in paragraph [274]. The Examiner is unable to find reference to this sequence in [274] in the preceding or subsequent paragraphs, so it is possible that [274] was added in error.
3. Claim Objections
A. Though not incorrect, the Examiner requests clarification for claims 2 and 4 regarding “at least one heavy-chain CDR2” (claim 2) and “at least one heavy-chain CDR3 (claim 4), since functional antibodies are known to have only a single heavy-chain CDR1, 2 and 3. The Examiner left a voicemail with Sunhee Lee on January 6, 2026 to request clarification. The call was not returned, nor does it need to be, as the attorney can simply provide comments in response to this Office Action.
B. For clarity, in claim 11, following all three recitations of “a bispecific antibody having”, the phrase should be amended to “IL-4Ra or of the antibody binding to IL-5Ra …”
C. Claim 17 is objected to since it should recite, for example, “administering to a subject”.
D. Claim 18 is objected to since the disease “Churg-Strauss syndrome” appears three times.
4. Claim Rejections - 35 USC § 112(a) – scope of enablement
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 17 and 18 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for treating the claimed diseases, does not reasonably provide enablement for preventing these diseases. 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 the invention commensurate in scope with these claims.
In In re Wands, 8USPQ2d, 1400 (CAFC 1988) page 1404, the factors to be considered in determining whether a disclosure would require undue experimentation include (1) the quantity of experimentation necessary, (2) the amount of 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.
The breadth of the claims is excessive with regard to claiming preventing the recited diseases. Neither the claims nor the specification provides a definition of “prevention”. Therefore, the Examiner is interpreting this as a disease will not occur in 100% of the subjects. Applicants provide no guidance or working examples of the ability of the claimed antibody to prevent any of the generic diseases in claim 18, nor the specific disease in claim 18. Furthermore, it is not predictable to one of ordinary skill in the art how to prevent these diseases by administering the recited antibody.
These factors lead the Examiner to hold that undue experimentation is necessary to practice the invention as claimed.
5. Claim Rejections - 35 USC § 112(a) – written description
Claims 1 and 7-10 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 7-10 are broadly drawn to antibodies comprising either a HCVR or LCVR. Claim 1 is included since it encompasses these claims. The specification only teaches that antibodies which specifically bind to IL-4Ra and IL-5Ra comprise both a heavy and light chain variable region, which comprise all 6 CDRs of antibodies recited in claims 2 and 4. The specification does not teach antibodies that comprise fewer than all 6 CDRs.
The nature of the invention is engineered antibodies where the relative level of skill of those in the art is deemed to be high. 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 routinely 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, William E.), 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).
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. 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. et al 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). Additionally, Bendig M. M. et al. 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).
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). While there are some publications which acknowledge that CDR3 is important, the conformations of other CDRs as well as framework residues influence binding. MacCallum et al. analyzed many different antibodies for interactions with antigen and state that although CDR3 of the heavy and light chain dominate, a number of residues outside the standard CDR definitions make antigen contacts (see page 733, right col.) and non-contacting residues within the CDRs coincide with residues as important in defining canonical backbone conformations (see page 735, left col.). The fact that not just one CDR is essential for antigen binding or maintaining the conformation of the antigen binding site, is underscored by Casset et al., which constructed a peptide mimetic of an anti-CD4 monoclonal antibody binding site by rational design and the peptide was designed with 27 residues formed by residues from 5 CDRs (see entire document). Casset et al. also states that although CDR H3 is at the center of most if not all antigen interactions, clearly other CDRs play an important role in the recognition process (page 199, left col.) and this is demonstrated in this work by using all CDRs except L2 and additionally using a framework residue located just before the H3 (see page 202, left col.).
In fact, even regarding CDR3, Scheffer et al. states “[t]herefore, many studies attempt to predict AIR-antigen binding exclusively based on the heavy/beta chain CDR3 sequences. Yet, the underlying rules determining whether an AIR can bind an antigen of interest remain unknown.” Furthermore, even within CDR3, Scheffer concludes “we have shown that there indeed exist motifs composed of a few amino acids in fixed positions of the antibody CDRH3, whose presence is nearly sufficient to predict antigen binding in a mutagenesis dataset where other variable regions were kept the same”. Applicants do not appear to show such a motif, nor would bind be predictable in the presence of changes to other CDRs.
Additionally, Valdes-Trescano (Section 2.3) states “[a]t the sequence region level, we observed a considerable variation in the accuracy of CDR modeling, especially for CDR3”.
Further, Chen et al. teach that the substitution of a single amino acid can totally ablate antigen and that the same substitution in closely related antibodies can have opposite effects binding (e.g., see entire document, including Figure I). For example, the authors compared the effects of identical substitutions in related antibodies DI6 and TI5, and as shown in Figure 3, some substitutions increased antigen binding in one antibody while ablating it in the other. As such, it is unpredictable which combination of random substitution has the recited function.
Finally, Ye teaches that “[t]he final data set contained 1157 antibodies and 57 antigens that were combined in 5041 antibody-antigen pairs. The best performance for the prediction of interactions was obtained by using the nearest neighbor method with the BLOSUM62 matrix, which resulted in around 82% accuracy on the full data set. These results provide a useful frame of reference, as well as protocols and considerations, for machine learning and data set creation in the prediction of antibody-antigen binding.
However, in this approach, “[s]everal machine learning approaches were compared to predict antibody-antigen interaction from protein sequences”. Therefore, even with a study using 1157 antibodies and 57 antigens, the best prediction was 82%. Again, it is noted that several machine learning approaches were used, showing that prediction can still be difficult and dependent on the prediction method used.
Thus, the state of the art recognized that it would be highly unpredictable that a specific binding member comprising an antibody comprising fewer than all of the six CDRs of a parental antibody with a desired specificity would retain the antigen-binding function of the parental antibody. One of ordinary skill in the art could not predictably extrapolate the teachings in the specification, limited to antibodies that comprise all 6 wild-type CDRs (i.e. HCVR and LCVR) to antibodies that comprise alterations in one or more CDRs from the parental antibody.
In summary, in view of the lack of the predictability of the art to which the invention pertains as evidenced by the above references, the lack of guidance and direction provided by applicant, and the absence of working examples, the Examiner concludes that undue experimentation would be required to practice the invention as claimed.
6. 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.
Claim 18 is 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.
The phrases “including” and “such as” render the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
7. 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.
A. Claims 1, 17 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Godar et al. in view of Stevens et al. (U.S. Patent No. 7,605,237) further in view of Takatsu et al. (U.S. Patent No. 5,453,491). The claim is drawn to a bispecific antibody that binds to both IL-4Ra of SEQ ID NO:65 and IL-5Ra of SEQ ID NO:66.
Godar teaches a bispecific antibody which targets both IL-4Ra (Abstract); however, the antibody targets IL-5 as opposed to IL-5Ra. Regardless, given the fact that it was known at the time of the instant invention to have targeted IL-5, it would have been obvious to have produced a bispecific antibody which targeted IL-5Ra since the motivation would have been to inhibit the effect of the interaction of IL-5 with its receptor, which either antibody would have accomplished. Godar also teaches this bispecific antibody to reduce lung inflammation and to treat asthma (last paragraph of Discussion).
Godar does not teach SEQ ID NO:65, nor SEQ ID NO:66. However, as seen below, Stevens teaches the IL-4 receptor of SEQ ID NO:65 and Takatsu teaches the IL-5 receptor of SEQ ID NO:66. Given this, it would have been obvious to have produced antibodies to both of these receptors, as it would serve the same purpose as the bispecific antibody of Godar.
SEQ ID NO:65
Patent No. 7605237
GENERAL INFORMATION
APPLICANT: Stevens, Sean
APPLICANT: Huang, Tammy T.
APPLICANT: Martin, Joel H.
APPLICANT: Fairhurst, Jeanette L.
APPLICANT: Raffique, Ashique
APPLICANT: Torres, Marcela
APPLICANT: Pobursky, Kevin J.
APPLICANT: Leidich, Raymond W.
APPLICANT: Windsor, Joan A.
APPLICANT: Mikulka, Warren R.
APPLICANT: Ahrens, Diana M.
APPLICANT: Shi, Ergang
APPLICANT: Papadopoulos, Nicholas J.
TITLE OF INVENTION: High Affinity Human Antibodies to Human IL-4 Receptor
FILE REFERENCE: 6030A
CURRENT APPLICATION NUMBER: US/11/906,517
CURRENT FILING DATE: 2008-03-11
PRIOR APPLICATION NUMBER: 60/848,694
PRIOR FILING DATE: 2006-10-02
PRIOR APPLICATION NUMBER: 60/957,738
PRIOR FILING DATE: 2007-08-24
NUMBER OF SEQ ID NOS: 590
SEQ ID NO 1
LENGTH: 207
TYPE: PRT
ORGANISM: homo sapiens
Query Match 100.0%; Score 1153; Length 207;
Best Local Similarity 100.0%;
Matches 207; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MKVLQEPTCVSDYMSISTCEWKMNGPTNCSTELRLLYQLVFLLSEAHTCIPENNGGAGCV 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MKVLQEPTCVSDYMSISTCEWKMNGPTNCSTELRLLYQLVFLLSEAHTCIPENNGGAGCV 60
Qy 61 CHLLMDDVVSADNYTLDLWAGQQLLWKGSFKPSEHVKPRAPGNLTVHTNVSDTLLLTWSN 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 CHLLMDDVVSADNYTLDLWAGQQLLWKGSFKPSEHVKPRAPGNLTVHTNVSDTLLLTWSN 120
Qy 121 PYPPDNYLYNHLTYAVNIWSENDPADFRIYNVTYLEPSLRIAASTLKSGISYRARVRAWA 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 PYPPDNYLYNHLTYAVNIWSENDPADFRIYNVTYLEPSLRIAASTLKSGISYRARVRAWA 180
Qy 181 QCYNTTWSEWSPSTKWHNSYREPFEQH 207
|||||||||||||||||||||||||||
Db 181 QCYNTTWSEWSPSTKWHNSYREPFEQH 207
SEQ ID NO:66
Patent No. 5453491
GENERAL INFORMATION
APPLICANT: Takatsu, Kiyoshi
APPLICANT: Tominaga, Akira
APPLICANT: Takagi, Satoshi
APPLICANT: Murata, Yoshiyuki
TITLE OF INVENTION: Human And Murine Interleukin-5 Receptor
CURRENT APPLICATION NUMBER: US/07/757,390
CURRENT FILING DATE: 10)SEP)1991
NUMBER OF SEQ ID NOS: 18
SEQ ID NO 14
LENGTH: 396
TYPE: PRT
Query Match 100.0%; Score 1728; Length 396;
Best Local Similarity 100.0%;
Matches 322; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DLLPDEKISLLPPVNFTIKVTGLAQVLLQWKPNPDQEQRNVNLEYQVKINAPKEDDYETR 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 21 DLLPDEKISLLPPVNFTIKVTGLAQVLLQWKPNPDQEQRNVNLEYQVKINAPKEDDYETR 80
Qy 61 ITESKCVTILHKGFSASVRTILQNDHSLLASSWASAELHAPPGSPGTSIVNLTCTTNTTE 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 81 ITESKCVTILHKGFSASVRTILQNDHSLLASSWASAELHAPPGSPGTSIVNLTCTTNTTE 140
Qy 121 DNYSRLRSYQVSLHCTWLVGTDAPEDTQYFLYYRYGSWTEECQEYSKDTLGRNIACWFPR 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 141 DNYSRLRSYQVSLHCTWLVGTDAPEDTQYFLYYRYGSWTEECQEYSKDTLGRNIACWFPR 200
Qy 181 TFILSKGRDWLAVLVNGSSKHSAIRPFDQLFALHAIDQINPPLNVTAEIEGTRLSIQWEK 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 201 TFILSKGRDWLAVLVNGSSKHSAIRPFDQLFALHAIDQINPPLNVTAEIEGTRLSIQWEK 260
Qy 241 PVSAFPIHCFDYEVKIHNTRNGYLQIEKLMTNAFISIIDDLSKYDVQVRAAVSSMCREAG 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 261 PVSAFPIHCFDYEVKIHNTRNGYLQIEKLMTNAFISIIDDLSKYDVQVRAAVSSMCREAG 320
Qy 301 LWSEWSQPIYVGNDEHKPLREW 322
||||||||||||||||||||||
Db 321 LWSEWSQPIYVGNDEHKPLREW 342
B. Claims 1 and 13-18 are rejected under 35 U.S.C. 103 as being unpatentable over Lee et al. in view of Stevens et al. (U.S. Patent No. 7,605,237) further in view of Takatsu et al. (U.S. Patent No. 5,453,491).
Lee teaches a bispecific (“dual-specific”) antibody (Abstract) comprising an anti-IL-4/IL-5 antibody (e.g. paragraph bridging both columns of page 624). Lee teaches that the IL-4 antibody blocks the interaction with IL-4Ra (first two lines of page 623). Regardless, given the fact that IL-4 and IL-5 produce their effects by binding to their respective receptors (IL-4Ra and IL-5Ra), it would have been obvious to have made antibodies to these receptors, as the effect of inhibiting either IL-4 and IL-5 or their respective receptors would have been expected to be the same.
Lee does not teach SEQ ID NO:65, nor SEQ ID NO:66. However, Stevens teaches the IL-4 receptor of SEQ ID NO:65 and Takatsu teaches the IL-5 receptor of SEQ ID NO:66. Given this, it would have been obvious to have produced antibodies to both of these receptors, as it would serve the same purpose as the bispecific antibody of Lee.
Claims 13-16 are taught under “Mutation scanning od anti-IL-4” (page 626), which disclose genes encoding the antibody VH and VL, along with vectors and host cells (see also “Antibody characterization” on the same page).
Regarding claims 17 and 18, Lee teaches blocking these cytokines have potential utility in treating allergic diseases such as asthma (last sentence on page 623).
C. Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over either Godar et al. or Lee et al., each in view of Stevens et al. and Takatsu et al. and either further in view of Patino et al.
The teachings of Godar, Lee, Stevens and Takatsu are seen in the above paragraphs of this section. None of the reference teaches targeting the D3 domain of SEQ ID NO:66.
However, Patino does teach the binding domain of IL-5Ra comprises D3 (e.g. first paragraph under “Results”; Figure 1). Therefore, it would have been obvious to target this domain in order to reduce binding of IL-5 to this receptor.
D. Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over either Godar et al. or Lee et al., each in view of Stevens et al. and Takatsu et al. and either further in view of Orcutt et al.
The teachings of Godar, Lee, Stevens and Takatsu are seen in the above paragraphs of this section. None of the reference teaches an IgG-scFv. However, Orcutt does (Abstract). It would have been obvious to have used the format of Orcutt to produce the IgG-scFv bispecific antibody of the either Godar or Lee.
E. Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over either Godar et al. or Lee et al., each in view of Stevens et al. and Takatsu et al. and either further in view of Egan et al. The teachings of Godar, Lee, Stevens and Takatsu are seen in the above paragraphs of this section. None of the reference teaches multispecific antibodies. However, Egan teaches that multispecific antibodies are potentially safer, more effective pharmaceuticals with higher stability than traditional antibodies (e.g. Abstract).
F. Claims 13-16 are rejected under 35 U.S.C. 103 as being unpatentable over Godar et al. in view of Stevens et al., further in view of Takatsu et al. and further in view of Lee et al.
The teachings of Godar, Stevens and Takatsu are seen in the above paragraphs of this section. None teach nucleic acids, vectors, host cells and methods of making a bispecific antibody. However, this is taught by Lee (“Mutation scanning od anti-IL-4”; page 626), which disclose genes encoding the antibody VH and VL, along with vectors and host cells (see also “Antibody characterization” on the same page). It would have been obvious to have used the nucleic acids, vectors and host cells of Lee for the production of essentially the same protein of Godar, especially given the fact that this technique was standard procedure in the art at the time.
8. Conclusion
A. Claims 1, 3, 7-18 are not allowable.
B. Claims 2 and 4-6 are objected to since they depend from rejected base claims.
Advisory information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ROBERT S LANDSMAN whose telephone number is 571-272-0888. The examiner can normally be reached M-F 8 AM – 6 PM (eastern).
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, Joanne Hama, can be reached at 571-272-2911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free).
/ROBERT S LANDSMAN/Primary Examiner, Art Unit 1647