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. Applicant’s election without traverse of Group V in the reply filed on 4/3/26 is acknowledged. Therefore, this restriction is deemed proper and is made FINAL.
B. Claims 1, 3, 7, 13, 15, 17, 18, 20-23, 25, 31, 35, 37, 39, 40 and 42-44 are pending. Claims 1, 3, 7, 13, 15, 17, 18, 20-23, 35, 37, 39, 42 and 43 are withdrawn as being drawn to non-elected inventions. Claims 25, 31, 40 and 44 are the subject of this Office Action.
2. Information Disclosure Statement
References 5, 6, 7, 8 and 9 on the IDS filed 11/6/23 have been lined through since the citations are incomplete.
3. Specification
A. In Example 7, the two primers, which are present in the Sequence Listing, need to be identified as SEQ ID NO:25 and 26, respectively.
B. The specification is objected to since the use of at least the term Tween® (both occurrences in the second paragraph of section 9.3 on page 60), which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks. The Examiner performed a cursory review, but Applicants are urged to perform a more thorough review of the specification.
4. Claim Rejections - 35 USC § 112(a) – scope of enablement
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.
Claim 31 is rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for epitopes with the intended use of treating an EBV infection, does not reasonably provide enablement for epitopes with the intended use of preventing EBV infection of a disease associated with EBV infection in a subject. 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 the intended use of preventing EBV infection. The Examiner has interpreted “preventing” as a condition will not occur in 100% of the subjects administered the intended compound. This is supported by paragraph [0269] of the published application, which defines “prevention” as “a method that is performed to prevent or delay the occurrence of a disease or disorder or symptom (e.g., EBV infection) in a subject.”
Paragraph [0002] of the published application discloses that EBV is associated with LPD in immunocompromised hosts and is associated with many different types of human B cell malignancies and epithelial cells malignancies.
However, Applicants provide no guidance or working examples of achieving prevention of any EBV-associated disease, including various cancers, or the actual entry of EBV into the cells of subject (i.e. “EBV infection” as exemplified in paragraph [0269]), nor is it predictable to one of ordinary skill in the art how to prevent EBV-associated diseases, nor an EBV infection from occurring in 100% of the subjects.
Cui (Abstract) teaches that EBV is associated with numerous diseases, but that no prophylactic vaccine exists –
Epstein-Barr virus (EBV) is the primary cause of infectious mononucleosis and has been strongly implicated in the etiology of multiple epithelial and lymphoid cancers, such as nasopharyngeal carcinoma, gastric carcinoma, Hodgkin lymphoma, Burkitt lymphoma, non-Hodgkin lymphoma and post-transplant lymphoproliferative disorder. There is currently no licensed prophylactic vaccine for EBV. Most efforts to develop prophylactic vaccines have focused on EBV gp350, which binds to CD21/CD35 to gain entry into B cells, and is a major target of serum neutralizing antibody in EBV seropositive humans. However, a recombinant monomeric gp350 protein failed to prevent EBV infection in a phase II clinical trial.
Regarding epitope-based therapies, Duralswamy et al. (Abstract) teaches that “epitope-based vaccination strategy designed to enhance Epstein-Barr virus (EBV)–specific CD8 cytotoxic T lymphocytes (CTLs) is increasingly being considered as a preferred approach for the treatment of EBV associated relapsed Hodgkin disease (HD) and nasopharyngeal carcinoma (NPC)”.
Furthermore, the post-filing reference by Andersen et al. provides numerous EBV-associated diseases in Tables 2-5, as well as various treatment regimens, including the use of acyclovir, valacyclovir, ganciclovir, corticosteroids, immunoglobulins, including rituximab.
However, while a reduction of symptoms is possible with various known treatments, including antibodies (which is pertinent here given that the claimed epitopes are intended to produce host antibodies against EBV), neither of Duralswamy, or Andersen, nor the specification, teach that any condition (e.g. cancer, infection) can be prevented.
Applicants may, without adding new matter, consider using a limitation such as “reducing the likelihood of”, or a similar phrase.
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
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.
Claims 25, 31, 40 and 44 are rejected under 35 U.S.C. 112, first paragraph, as containing 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(s), at the time the application was filed, had possession of the claimed invention.
These are genus claims. The claims are drawn to isolated epitopes located within either region 341-362 or 528-616 of an EBV gB protein, wherein, other than either 3, or 4 residues, respectively, which must be maintained, can have a “substitution, addition or deletion of one or several amino acid residues” (i.e. a “variant” as recited in the claims).
It is noted that the epitope of the first part of claim 25 is up to 22 residues, whereas the epitope of the second is 89 residues. While the artisan could envision every possible epitope, the number of possible variants could essentially be 2019 for part 1 (not including positions 352, 356 and 360), and 2085 for part 2 (not including residues 540, 567, 610 and 613).
Given this, the complexity of the issue is magnified by the fact that the claims recite that the epitope “retains a biological function of the epitope peptide from which it is derived”. Paragraphs [0010]-[0014] of the specification defines “biological function” as -
includes but is not limited to one or more selected from the following:
1) specifically binding to monoclonal antibody 3A3 (e.g., that has heavy chain CDRs set forth in SEQ ID NOs: 3-5 and light chain CDRs set forth in SEQ ID NOs: 6-8);
2) an ability to induce in a subject an antiserum capable of neutralizing EBV, and/or blocking or inhibiting the fusion of EBV with a cell (optionally, after the fusion of the epitope peptide with a carrier protein);
3) an ability to induce an antibody response for effectively clearing EBV and an EBV-infected cell in vivo (optionally, after the fusion of the epitope peptide with a carrier protein); and
4) an ability to prevent and/or treat an EBV infection or a disease associated with EBV infection in a subject (optionally, after the fusion of the epitope peptide with a carrier protein).
It is noted that the definition recites “includes but in not limited to”, therefore, binding any antibody can be considered a biological function.
Regarding the effect of mutations on epitope function, the post-filing reference by Khatamzas teaches that “immunity can be jeopardized by the emergence of immune escape mutations in T cell epitopes” since “the mechanisms of reduced T cell recognition include mutations in the epitope region, which is recognised by the T cell receptor or in the anchor residues of the viral peptide that binds to the MHC molecules interfering with antigen presentation, as well as other escape pathways such as mutations affecting proteasomal processing”.
Thus, the scope of the claims includes numerous structural variants, and the genus is highly variant because a significant number of structural differences between/among genus members is permitted. Although these types of changes are routinely done in the art, the specification and claims do not provide any guidance as to what changes should be made, other than retaining one or more of the residues indicated in the claims. Otherwise, structural features that could distinguish compounds in the genus from others in the nucleic acid or protein class are missing from the disclosure. Other than the retention of 3 or 4 residues, no common structural attributes identify the members of the genus.
Though claim 31 is not drawn to treatment, it is noted that, as shown in Figure 11, and as discussed in Example 9.2, the critical residues at positions 352, 356 and 360 were only identified by Western blot analysis using mouse monoclonal antibody 3A3, whereas critical residues 540, 567, 610 and 613 were only identified using mouse monoclonal antibody 3A5. No treatment using these mutated epitopes has been shown to be effective, only that these residues were critical for the binding of a murine antibody to the human protein epitope.
The general knowledge and level of skill in the art do not supplement the omitted description because specific, not general, guidance is what is needed. Since the disclosure fails to describe the common attributes or characteristics that identify members of the genus, and because the genus is highly variant, an epitope with only 3 or 4 wild-type residues retained, alone, is insufficient to describe the genus. One of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus. Thus, Applicant was not in possession of the claimed genus at the time the invention was made.
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.
Claims 25, 31, 40 and 44 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.
In claims 25, 40 and 44, the phrase "e.g." renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
In claim 31, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
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.
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/ROBERT S LANDSMAN/Primary Examiner, Art Unit 1647
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