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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on Nov. 12, 2025 has been entered.
DETAILED ACTION
Acknowledgement is hereby made of receipt and entry of the communication filed on Nov. 12, 2025. Claims 2-5, 11-12 and 14-17 are pending and currently examined.
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 4-5 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 4-5 are directed to a method for generating a polyclonal antibody, or for generating a polyclonal immune serum, that is specific for or specifically binds to an epitope, the method comprising administering to or immunizing a subject with a chimeric or recombinant polypeptide comprising a portion of a first polypeptide from a first species and at least one portion of a second polypeptide from a second species, wherein the at least one portion of the second polypeptide is a homologue of the first polypeptide, and wherein the at least one homologous portion of the second polypeptide comprises an epitope which is not present in the first polypeptide, and further wherein at least about 80% to about 99% of the amino acid sequence of the chimeric or recombinant polypeptide is amino acid sequence from the first species and between about 1% to about 20% of the amino acid sequence of the chimeric or recombinant polypeptide is amino acid sequence from the second species.
The claims specify “wherein the at least one portion of the second polypeptide is a homologue of the first polypeptide”. This limitation is not clear. Neither the Specification nor the claims clearly define the term “homologue”. Instead, Applicant states in the response filed on Nov. 12, 2025, that, by standard molecular biology definition, a “homologue” is a protein or polypeptide that shares sequence similarity due to common evolutionary origin, typically retaining structural and functional features across species. See page 16. However, it is not clear how a portion of a protein can be a “homologue” of protein of another species as a whole, as recited in claim 4 “wherein the at least one portion of the second polypeptide is a homologue of the first polypeptide”, especially when the claims specify that the sequence from the second species (second polypeptide) can be as low as 1% of the whole recombinant protein. In other words, it is how clear how to determine if a second polypeptide sequence that is only about 1% in size of a first polypeptide sequence is a “homologue” of the first polypeptide or not.
To facilitate examination, the limitation “wherein the at least one portion of the second polypeptide is a homologue of the first polypeptide” is considered as if it were ““wherein the second polypeptide is a homologue of the first polypeptide”.
It is noted any interpretation of the claims set forth above does not relieve Applicant of the responsibility of responding to this rejection. If the actual interpretation of the claims is different than that posited by the Examiner, additional rejections and art may be readily applied in a subsequent final Office action.
Claim Rejections - 35 USC § 102/103
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 2-5 and 11-12 are rejected under 35 U.S.C. 102/103 as being unpatentable over Baert et al. (N Engl J Med 2003; 348: 601-8).
Claims 4-5 are directed to a method for generating a polyclonal antibody, or for generating a polyclonal immune serum, that is specific for or specifically binds to an epitope, the method comprising administering to or immunizing a subject with a chimeric or recombinant polypeptide comprising a portion of a first polypeptide from a first species and at least one portion of a second polypeptide from a second species, wherein the at least one portion of the second polypeptide is a homologue of the first polypeptide, and wherein the at least one homologous portion of the second polypeptide comprises an epitope which is not present in the first polypeptide, and further wherein at least about 80% to about 99% of the amino acid sequence of the chimeric or recombinant polypeptide is amino acid sequence from the first species and between 1% to about 20% of the amino acid sequence of the chimeric or recombinant polypeptide is Amino acid sequence from the second species.
Claims 2-3, 11 and 12 specify that the first species is the subject’s species, and that the polypeptide from the second species is a homologue of the polypeptide from the first species.
Here, the claimed chimeric or recombinant polypeptide reads on a chimeric (e.g. mouse-human) monoclonal antibody which induces anti-antibody immune response.
Baert teaches that treatment with infliximab, a chimeric monoclonal IgG1 antibody against tumor necrosis factor, can result in the formation of antibodies against infliximab. The authors evaluated the clinical significance of these antibodies in patients with Crohn’s disease. In a cohort of 125 consecutive patients with Crohn’s disease who were treated with infliximab infusions, they evaluated the concentrations of infliximab and of antibodies against infliximab, clinical data, and side effects (including infusion reactions). Antibodies against infliximab were detected in 61 percent of patients. See Abstract.
Accordingly, while teaching a method of treating patients with Crohn’s disease by administration of a mouse-human chimeric antibody, infliximab, Baert also teaches a method of inducing host immune response in human subjects against the chimeric antibody, as a side effect.
A schematic structure of the mouse-human chimeric antibody infliximab is shown below:
PNG
media_image1.png
300
334
media_image1.png
Greyscale
Its variable regions (VL and VH) are from the mouse Mab (a second species), which is considered as replacing the corresponding homologous human variable regions of the human Ig framework which contributes the constant regions (a first species).
Regarding claims 4-5, which specify further wherein at least about 80% to about 99% of the amino acid sequence of the chimeric or recombinant polypeptide is amino acid sequence from the first species and between 1% to about 20% of the amino acid sequence of the chimeric or recombinant polypeptide is amino acid sequence from the second species, infliximab contains the entire constant regions of the IgG light and heavy chains from human origin and only the variable regions from mouse origin. It is known in the art that an IgG heavy chain is normally between about 450 and 550 amino acids in length while the variable region of an IgG heavy chain is normally between 100 and 110 amino acids in length. Therefore, the infliximab is expected to comprise a chimeric polypeptide, the mouse-human IgG heavy chain, comprising at least about 80% of amino acid sequence from human origin.
Accordingly, Baert anticipates and/or makes obvious claims 2-5, 11 and 12.
Response to Applicant’s Arguments
Applicant’s arguments filed on Nov. 12, 2025 have been fully considered. Arguments relating to withdrawn rejections are moot. Applicant’s arguments relevant to the current rejections are addressed as follows.
To the 102/103 rejection of claims 2-5 and 11-12, over Baert et al., applicant argues:
(1) that Baert reports a clinical investigation of infliximab therapy in patients with Crohn's disease and observes unintended anti-drug antibody formation, that the study neither teaches nor suggests the deliberate construction of recombinant or chimeric immunogens for generating polyclonal antibodies, that the immune response described in Baert is incidental and undesired, arising as a side effect of therapeutic administration, that the present invention resides in the field of protein engineering and immunochemistry, where immunogenicity is intentionally and precisely directed to elicit antibodies against specific epitopes, and that, accordingly, Baert does not disclose any method "for generating a polyclonal antibody or immune serum," as recited in the claims.
(2) that the structure of infliximab differs fundamentally from the chimeric or recombinant polypeptides required by the present claims, that infliximab is a chimeric monoclonal antibody comprising approximately 75% human and 25% murine amino acid sequence, constructed by replacing entire murine variable domains into a human antibody scaffold (see Ridder et al., JPNG, 45:3-14 (2007), attached hereto), that this domain-level replacement produces a molecule composed of large sequence segments from two species, in roughly a three-to-one ratio, that this structural configuration is not comparable to the defined and limited epitope-level substitutions now expressly required by amended claim 4, which specify that only about 1% to about 20% of the amino acid sequence is heterologous, that the present invention requires insertion or replacement of small, homologous sequence segments corresponding to selected epitopes within a predominantly self-derived backbone, and that Infliximab, by contrast, incorporates full murine domains without regard to homologous alignment or epitope targeting and thus does not meet the claim requirement for homologous epitope grafting.
(3) that the objective of infliximab's design was to reduce immunogenicity by humanizing a murine antibody for therapeutic use, whereas the present invention seeks to harness immunogenicity in a controlled and specific manner to generate defined polyclonal antibody responses, that there is no disclosure or motivation in Baert to construct an immunogen containing 80-99% self-sequence and 1-20% heterologous epitope sequence for antibody generation (claim 4) or a construct where the amino acid sequence of the chimeric or recombinant polypeptide at least about 80% identical to the amino acid sequence of the polypeptide from the first species (claim 11), and that the therapeutic administration of infliximab to patients, resulting in unpredictable and undesired anti-drug antibodies, cannot reasonably be interpreted as teaching or suggesting the purposeful immunization strategy and structural design now claimed.
Applicant’s arguments are not persuasive. Regarding argument (1), intended or not, Baert teaches a method of administering to a subject Infliximab which comprises the same step and generate the same result as claimed (generating a humoral immune response). Therefore, Baert teaches a process that is indistinguishable from the invention claimed.
Regarding argument (2), it is noticed that claim 4 recites “further wherein at least about 80% to about 99% of the amino acid sequence of the chimeric or recombinant polypeptide is amino acid sequence from the first species and between 1% to about 20% of the amino acid sequence of the chimeric or recombinant polypeptide is amino acid sequence from the second species.” First, neither the specification nor the claims make it clear what the term “about 80%” encompasses. As argued by Applicant based on teachings in Ridder et al., Journal of Pediatric Gastroenterology and Nutrition, 45:3-14 (2007), Infliximab is a chimeric monoclonal antibody (75% human, 25% murine) against tumor necrosis factor-a. Here, the ratio of 75% can be considered as “about 80%.” Secondly, there is a certain level homology between antibody variable regions of human and mouse origins. This homology when added to the overall homology of the chimeric IgG polypeptide would be expected to increase the 75% of the human sequence (mostly composed of the constant regions) taught in Ridder et al. to “at least about 80%.”
Additionally, the claims, as currently presented, do not exclude incorporating full murine domains (e.g., the variable regions), and the murine variable regions are regarded as being homologous the counterpart variable regions of human origin.
Regarding argument (3), first, the objective of infliximab's design is not relevant of the claimed invention since the infliximab has the structural features of the polypeptide as claimed and since the administration of infliximab to a human subject is indistinguishable from the claimed method. Secondly, as to the argument that the present invention seeks to harness immunogenicity in a controlled and specific manner to generate defined polyclonal antibody responses, this argument does not change the fact that the claimed method comprises administration of a chimeric or recombinant polypeptide to a host subject to generate antibodies. Baert teaches a method that comprises the same process and results in generating antibodies. Since infliximab is expected to have the same structural characteristics of the chimeric or recombinant polypeptide as claimed, there is no need for a motivation to modify the chimeric antibody infliximab.
Additionally, Applicant’s arguments that the therapeutic administration of infliximab to patients, resulting in unpredictable and undesired anti-drug antibodies, cannot reasonably be interpreted as teaching or suggesting the purposeful immunization strategy and structural design now claimed is not germane to the current rejection since Baert already teaches an immunization process that is indistinguishable from the invention claimed.
Conclusion
No claims are allowed.
Claims 14-17 are objected to for depending from a rejected claim.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NIANXIANG (NICK) ZOU whose telephone number is (571)272-2850. The examiner can normally be reached on Monday - Friday, 8:30 am - 5:00 pm, EST. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, MICHAEL ALLEN, on (571) 270-3497, can be reached. 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). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/NIANXIANG ZOU/
Primary Examiner, Art Unit 1671