DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2 Applicant's amendment, filed on 02/01/2024, is acknowledged.
3. Claims 1-17 are pending and under examination.
4. Applicant’s IDS, filed 02/01/2024, 03/29/2024, 05/23/2025, 08/08/2025, is acknowledged.
5. The following is a quotation of 35 U.S.C. 112(b) (Pre AIA , 35 U.S.C. 112, second paragraph):
(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.
6. Claim 9 is rejected under 35 U.S.C. 112(b), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
(i) The recitation "preferably ..." in claim 9 is indefinite because the narrow range within the broad range using the term “preferably” renders the claim indefinite.
7. The following is a quotation of 35 U.S.C. 112(a) (Pre-AIA 35 U.S.C. 112, first paragraph):
(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.
8. Claims 1, 3-5, 7-17 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 encompass a broad genus of anti-PD-L1 nanobody comprising mixing and matching between different CDRs from different clones binding different epitopes having different binding affinities; as well as up to three amino acid modification in the CDRs.
Claims 5 and 7 encompass a broad genus of anti-PD-L1 nanobody comprising up to 15% modification the VHH of SEQ ID NOs: 4, 8, 12, 13, 15 including their CDRs.
Claim 9 encompasses a broad genus of antigen-targeting protein different from PD-L1.
Claim 10 encompasses a broad genus of functional small molecules.
Claim 11 encompasses a broad genus of polynucleotide encoding defined anti-PD-L1 nanobody and undefined Fc region, cytokine regulatory protein, antigen-targeting proteins and functionl small molecule.
Claim 13 encompasses the host cell that do not express the anti-PD-L1 nanobody, i.e., host cell comprises the isolated polynucleotide without promotor and enhancer.
However, there does not appear to be an adequate written description in the specification as-filed of the essential structural feature that provides the recited function of binding PD-L1 and treating and preventing each and every disease. The Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, ¶ 1 "Written Description" Requirement make clear that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the genus.
Clone CDR1-3 CDR1 CDR2 CDR3
Antibody 1 1-3 GRSFSSSG INSSGGDT AAKEGGGPSSIPAIYDY
Antibody 2 5-7 GFTFSSYA INTGSEIV ATGLVSAEHDGI
Antibody 3 9-11 GRDFLTYG INWSGSMT AARRGAVTYASSNEYEH
Antibody 4 9-11 GRDFLTYG INWSGSMT AARRGAVTYASSNEYEH
Antibody 5 1, 2, 14 GRSFSSSG INSSGGDT AAKEGGGPSSIPAIFDY
The specification under example 1 provided 5 positive clones with high expression were obtained and designated antibody 1-antibody 5 [0084]-[0085].
Clone SEQ ID NO CDR1-3 SEQ ID NOs Humanized SEQ ID NO
Antibody 1 4 1-3 1hu 28
Antibody 2 8 5-7 2hu 29
Antibody 3 12 9-11 3hu 30
Antibody 4 13 9-11 4hu 31
Antibody 5 15 1, 2, 14 5hu 32
Example 2 discloses the binding activity of the different antibodies to different antigens was determined [0087].
The Experimental results show that the antibodies and humanized version thereof prepared can all block the binding of the antigen PD-1 to its ligand PD-L1 (i.e., PD-1/PD-L1) [0104], [0126]. Also, the experimental results show that the antibodies and humanized version thereof provided can all well block the binding of antigen-human CD-80 [0108], [0113] and [0130].
The results show that after treatment with different antibody drugs, the tumor volume of each experimental mouse was significantly inhibited, each antibody drug exhibited goo tumor-inhibiting effect [0133].
The specification discloses only 4 species (nanobodies 3 and 4 have identical CDRs) within the instant claim scope. The instant application encompasses (but does not exemplify) fragments and CDRs modification up to 15% (deletion/addition/substitution) to the claimed HCDRs of SEQ ID NOs: 1-3, 5-7, 9-11, 1-2, 14. There is no teaching identifying what amino acids can be varied within the VH-CDRs nanobody regions and still retain antibody or fragments capable of binding PD-L1. Brown et al (J. Immuno. 1996 May, 3285-91 at 3290 and Tables 1 and 2) describes how a one amino acid change in the VH CDR2 of a particular antibody was tolerated whereas, the antibody lost binding upon introduction of two amino changes in the same region. Vajdos et al. (J. Mol. Biol. 2002, Jul 5, 320(2):415-28 at 416) teach that amino acid sequence and conformation of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. Aside from the CDRs, the Fv also contains more highly conserved framework segments which connect the CDRs and are mainly involved in supporting the CDR loop conformations, although in some cases, framework residues also contact antigen. The scope of the claims encompasses antibodies with VH or VL that encompass variation (addition, deletion, substitution) in their CDRs. The prior art discloses that 6 CDRs as being essential structure of antibody's binding site, and thus when intact, would provide enough structure to define the antibody's binding site (structure/function correlation) e.g., where amino acid substitutions can be made so as to change (e.g. 6CDR's) or retain (e.g., constant or variable framework) antigen binding. Neither the prior art nor applicant's disclosure defines sufficient representative antibodies and/or sufficient structure/function correlation between modifying the VHCDRs regions of the disclosed nanobody and the retention of a specific binding antibody that binds the PD-L1 to satisfy the WD requirement for the claims.
Neither the specification, nor the prior art provides any examples to support the premise of mixing and matching a HCDR of the VH of different nanobodies would result in antigen binding. The prior art does not support a definition of an antibody structure by mixing and matching the HCDR1-3 sequence of a VHH would result in functional anti-PD-L1 nanobody. The specification fails to show that all HCDR1, HCDR2, HCDR3 of the anti-PD-L1 nanobodies are equivalent and therefore interchangeable. The specification fails to establish that by replacing at least one CDR of nanobody 3 with another CDR from nanobody 1-2 and 4-5 maintains PD-L1 binding. Mixing and matching different the CDRs from different anti-PD-L1 nanobodies has not been shown to lead to PD-L1 binding. Such teachings were not made part of the specification at the time the invention was made.
It is unlikely that nanobodies as defined by the claims which may contain less than the full complement of CDRs from the heavy variable regions of the nanobody -15 fused to framework sequence, have the required binding function. The specification provides no direction or guidance regarding how to produce nanobodies as broadly defined by the claims. Undue experimentation would be required to produce the invention commensurate with the scope of the claims from the written disclosure alone. Further, the specification does not teach that a functional nanobody can be obtained by replacing the CDR regions of an acceptor antibody with the less than all the 3 CDRs sequences of a donor nanobody as is evidenced by the humanized nanobodies 1hu-5hu. 1hu-5hu comprises the whole set of the 3 CDRs of the nanobodies 1-5, respectively.
With respect to the recitation a nanobody which does not comprise all 3 CDRs of the nanobody 1-5, the Examiner directs Applicant's attention to the training material given by Bennett Celsa, Example 2: (Ab genus: modified CDR's) slides 34-40. Example 2 of the Training material ((https://www.aipla.org/docs/default-source/committee-documents/bcp-files/2020/uspto-bcp-antibody-slides-final.pdf?sfvrsn=b377f2cc_0) which requires that the claims explicitly recite the binding antigen in addition to all 6 CDR regions for fulfillment of the written description requirements under § 112, 1. Slide 39 indicates that a claim encompasses antibodies with 6 intact CDRs as well as a subgenus of antibodies that encompass up to 10% variation (fragments and/or analogs) in the 6 CDRs lacks written description. Slide 40 provide the conclusion that, a single antibody species would not be deemed by one of skill in the art to be representative of a claim that defines an antibody that binds antigen X comprising at least 90% homology to the 6 CDR of the VH and VL chains.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the written description inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116.). Consequently, Applicant was not in possession of the instant claimed invention. See University of California v. Eli Lilly and Co. 43 USPQ2d 1398.
Applicant is invited to point to clear support or specific examples of the claimed invention in the specification as-filed.
9. Claims 14 and 17 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 a method of treating breast cancer with the anti-PD-L1 nanobodies recited in the claim, does not reasonably provide enablement for methods for preventing and/or treating each and every disease with the claimed anti-PD-L1 nanobodies. 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 and use the invention commensurate in scope with these claims.
Claim 17 encompasses a broad genus of method of treating/preventing each and every disease with the claimed anti-PD-L1 nanobodies.
Besides, breast cancer, any treatment using the anti-PD-L1 nanobodies is not yet known and has not yet been disclosed, therefore, the methods is only potential because it is not currently available in practical form.
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized In re Wands (858 F2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)). The factors most relevant to this rejection are the scope of the claim, the amount of direction or guidance provided, the lack of sufficient working examples, the unpredictability in the art and the amount of experimentation required to enable one of skill in the art to practice the claimed invention.
The claimed method of producing a nanobody or fusion protein by culturing a host cell of claim 13 would not result in the production of the nanobody or the fusion protein because the host cell comprising the polynucleotide does not contain an enhancer and a promoter to express the polynucleotide comprising the anti-PD-L1 nanobodies.
The specification under example 7 the inoculation of humanized PD-L1 tumor cell line MC-38-hPD-L1 KL3# were inoculated subcutaneously into the right scapula sites of a PD-L1 humanized transgenic mouse model of hPD-L1-C57BL/6 female mice. The results show that after treatment with different antibody drugs, the tumor volume of each experimental mouse was significantly inhibited; each antibody drug exhibited a goo tumor-inhibiting effect.
Regarding in vivo methods which rely on generally unpredictable mechanisms, ''The amount of
guidance or direction needed to enable the invention is inversely related to the amount of
knowledge in the state of the art as well as the predictability in the art.'' In re Fisher, 427 F.2d
833, 839, 166 USPQ 18, 24 (CCPA 1970). The "amount of guidance or direction'' refers to that information in the application, as originally filed, that teaches exactly how to make or use the
invention. The more that is known in the prior art about the nature of the invention, how to make,
and how to use the invention, and the more predictable the art is, the less information needs to be
explicitly stated in the specification. In contrast, if little is known in the prior art about the nature
of the invention and the art is unpredictable, the specification would need more detail as to how
to make and use the invention in order to be enabling (MPEP 2164.03).'' The MPEP also states
that physiological activity can be considered inherently unpredictable.
Further, in Rasmusson v. SmithKline Beecham Corp., 75 USPQ2d 1297-1303 (CAFC 2005), the
court states "If mere plausibility were the test for enablement under section 112, applicants could
obtain patent rights to "inventions" consisting of little more than respectable guesses as to the
likelihood of their success. When one of the guesses later proved true, the 'inventor' would be
rewarded the spoils instead of the party who demonstrated that the method actually worked. That
scenario is not consistent with the statutory requirement that the inventor enable an invention
rather than merely proposing an unproved hypothesis."
The influence of a scientific theory should depend on its empirical and demonstrable aspects and
not its underlying logic. Yet such empirical and demonstrable aspects of the claimed method of
treating or preventing each and every disease by administering anti-PD-L1 nanobody are lacked in the instant specification. No working empirical data demonstrating the effect of anti-PD-L1 nanobodies would treat each and every disease. The skill in the art would doubt that the claimed administration of anti-PD-L1 nanobodies would treat each and every disease.
Xu-Monette et al (Front. Immuno. 8:1597, 2017) teach that neither PD-1 nor PD-L1 expression
is specific for the reversible T cell dysfunction state, and the effect of PD-1/PD-L1 blockade can
be context-dependent. In addition, PD-1 signaling and the mechanism of action of anti-PD-1/L1
mAbs are not completely understood (see page 1, 1st ¶ under Introduction). Further, Xu-Monette
teaches that a large proportion of patients, including those with PD-L1+/PD-1+ expression, do
not respond to PD-1/PD-L1 blockade (see page 2, left col., 1st ¶). Xu-Monette et al teach that in
preclinical models, comparison between PD-1 blockade and PD-L1 blockade showed
inconsistent or contradictory results. Several studies demonstrated that PD-1 and PD-L1
blockade had similar efficacy in preclinical models with PD-L1+ tumors. In tumor-formation
mouse models, PD-1 blockade showed striking efficacy in inhibiting hematogenous
dissemination of tumor cells with poor immunogenicity, but PD-L1 blockade had no effect (page
8, right col., 3rd ¶). Xu-Monette et al teach that these contradictory results suggest that PD-L1
interactions with PD-1, CD80, and other unknown receptors have context-dependent functions
(page 6, right col., 2nd ¶). Xu-Monette et al summarize the paradoxical results in studies of PD-
1/PD-L1 and PD-1/PD-L1 blockade, this review discussed a few open questions from
mechanistic and clinical perspectives.
Xu-Monette et al teach that both PD-1 and PD-L1 can either dependently or independently drive
immune suppression. Whether tumor or host factors dictate immunity remains to be determined.
Mechanisms that are not completely understood also include those governing PD-1 expression,
molecular pathways underlying PD-1/PD-L1 blockade, the difference in PD-1 signaling upon
PD-L1 binding and upon anti-PD-1 mAb binding, metabolic crosstalk between tumor cells and
T cells, and functional relationship (causal, consequential, or independent) between PD-1/PD-L1
expression and cell metabolism. Molecular delineation and critical node identification may also
help clarify the inconsistent preclinical results of blocking PD-1 compared with blocking PD-L1
(page 19, left col., 1st ¶). Xu-Monette et al teach that it is unclear whether the minor role of the
oncogenic PD-L1 expression in the BRAF.PTEN melanoma model applies to tumor PD-L1
expression upregulated by other tumor-intrinsic mechanisms in different types of cancer (see
page 4, left col., 2nd ¶).
However, in view of the lack of predictability of the art to which the invention pertains the lack
of established clinical protocols for effective immune checkpoint-based therapies, undue
experimentation would be required to practice the claimed methods with a reasonable
expectation of success, absent a specific and detailed description in applicant’s specification of
how to effectively practice the claimed methods and absent working examples providing
evidence which is reasonably predictive that the claimed methods are effective for treating/preventing diseases.
The MPEP states that the issue of "correlation" is also dependent on the state of the prior art. In
other words, if the art is such that a particular model is recognized as correlating to a specific
condition, then it should be accepted as correlating unless the examiner has evidence that the
model does not correlate. Even with such evidence, the examiner must weigh the evidence for
and against correlation and decide whether one skilled in the art would accept the model as
reasonably correlating to the condition. See MPEP 2164.02.
The scope of the required enablement varies inversely with the degree of predictability involved,
but even in unpredictable arts, a disclosure of every operable species is not required. A single
embodiment may provide broad enablement in cases involving predictable factors, such as
mechanical or electrical elements...However, in applications directed to inventions in arts where
the results are unpredictable, the disclosure of a single species usually does not provide an
adequate basis to support generic claims.” MPEP § 2164.03.
The burden of enabling the prevention of a disease (i.e. the need for additional testing) would be greater than that of enabling a treatment due to the need to screen those mammals susceptible to such diseases and the difficulty of proof that the administration of the drug was the agent that acted to prevent the condition. Further, the specification does not provide guidance as to how one skilled in the art would go about screening those patients susceptible to a disease including breast cancer within the scope of the presently claimed invention. Nor is sufficient guidance provided as to a specific protocol to be utilized in order to prove the efficacy of the presently claimed anti-PD-L1 nanobody in preventing a disease state including breast cancer. For example, the specification discloses that the experimental mice with MC-38-hPD-L1 KL3# were injected intraperitoneal (i.p.) with anti-PD-L1 nanobody. (e.g. see page 31/example 7of the instant specification). The specification does not show that anti-PD-L1 nanobody being injected prior to the breast cancer establishment. Therefore, the specification at most discloses a method of treating breast cancer by administering anti-PD-L1 nanobody but not preventing each and every disease.
Reasonable correlation must exist between the scope of the claims and scope of the enablement set forth. In view on the quantity of experimentation necessary the limited working examples, the nature of the invention, the state of the prior art, the unpredictability of the art and the breadth of the claims, it would take undue trials and errors to practice the claimed invention.
10. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
11. Claims 1-17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 4-8, 10, 11, 18-20, 26 and 30-40 of copending Application No. 18692312 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the `312 application are directed to bispecific antibody, wherein the bispecific antibody comprises a first antigen-binding moiety and a second antigen-binding moiety comprising anti-PD-L1 nanobody comprising claimed/referenced SEQ ID NOs: 4/83, 28/87 (comprising SEQ ID NOs: 1-3), 8/82, 29/88 (comprising SEQ ID NOs: 5-7), 12/84, 30/89 (comprising SEQ ID NOs: 9-11), 13/85, 31/90 (comprising SEQ ID NOs: 9-11), 15/86, 32/91(comprising SEQ ID NO: 1, 2, 14). The `312 application also claims methods for producing the bispecific antibody and methods for preventing and/or treating a disease with the bispecific antibody.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
12. No claim is allowed.
13. The anti-PD-L1 nanobodies comprising the CDRs of SEQ ID NO: 1-3, 5-7, 9-11, and 1-2, 14 are free from prior art. Further, the anti-PD-L1 nanobody comprising SEQ ID NOs: 4, 8, 12, 13, 15, 28-32 are free from prior art.
14. Any inquiry concerning this communication or earlier communications from the examiner should be directed to MAHER M HADDAD whose telephone number is (571)272-0845. The examiner can normally be reached on Monday-Friday from7:00AM to 4:30PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu, can be reached at telephone number 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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June 29, 2026
/MAHER M HADDAD/ Primary Examiner, Art Unit 1644
Prosecution Insights