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 03/14/2024, is acknowledged.
3. Claims 1-2, 4-8, 10-11, 18-20, 26 and 30-40 are pending and under examination.
4. Applicant’s IDS, filed 03/14/2024, 03/29/202, 05/23/2025, 08/08/2025, is acknowledged.
5. 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.
6. Claims 1-2, 4-8, 10-11, 18, 26 and 30-40 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 26 encompasses a broad genus of monoclonal antibodies comprising up to three amino acid modifications in the H/LCDRs of SEQ ID NOs:1-35 without antigen specificity.
Claim 30 encompasses a broad genus of monoclonal antibodies that comprising up to three amino acid modifications in the H/LCDRs of SEQ ID NOs: 1-35 (m212, m305, m107, m202, m301, m109) as well as up to 20% variations in the VH and VL of SEQ ID NOs 36-69.
Claim 31 encompasses a genus of monoclonal antibodies comprising the VH and VL of SEQ ID NOs: 36/48, 37/49, 38/50, 39/51, 40/52, 41/53, 42/54, 43/55, 44/56, 45/57, 46/58, 47/59 without antigen specificity.
Claim 1 encompasses a broad genus of bispecific anti-TGF-β, GARP and GARP-TGF-β antibodies comprising mixing and matching different heavy chains and light chains CDRs of different antibodies that binds different epitope and different target antigens of TGF-β, GARP and GARP-TGF-β; as well as comprising up to two modifications in the H/LCDRs of SEQ ID NOs:1-35 (m212, m305, m107, m202, m301, m109 or humanized version thereof) and broad genus of anti-PD-L1 antibodies.
Claim 2 encompasses broad genus of bispecific anti-TGF-β, GARP and GARP-TGF-β antibodies comprising up to two amino acid modifications in the VH/VL CDRs of SEQ ID NO: 1-35 and broad genus of anti-PD-L1 antibodies.
Claim 4 encompasses broad genus of bispecific anti-TGF-β, GARP and GARP-TGF-β antibodies comprising up to two amino acid modifications in the VH/VL CDRs of SEQ ID NO: 1-35 as well as up to 20% variations in the VH and VL of SEQ ID NOs: 36-59 and broad genus of anti-PD-L1 antibodies.
Claim 4 encompasses broad genus of bispecific anti-TGF-β, GARP and GARP-TGF-β antibodies comprising mixing and matching VH and VL of SEQ ID NOs: 36-59 from different antibodies that binds different epitopes and different target antigens TGF-β, GARP and GARP-TGF-β and broad genus of anti-PD-L1 antibodies.
Claim 5 encompasses broad genus of bispecific anti-TGF-β, GARP and GARP-TGF-β antibodies comprising mixing and matching VH and VL of SEQ ID NOs: 36-41/42-47 and SEQ ID NO: 48—53/54-59 from different antibodies that binds different epitopes and different target antigens TGF-β, GARP and GARP-TGF-β and broad genus of anti-PD-L1 antibodies.
Claim 6 encompasses broad genus of bispecific anti-TGF-β, GARP and GARP-TGF-β antibodies as recited in claim 1 and broad genus of anti-PD-L1 single-domain antibodies.
Claim 7 encompasses broad genus of bispecific anti-TGF-β, GARP and GARP-TGF-β antibodies as recited in claim 1 and broad genus of anti-PD-L1 single-domain antibodies comprising mixing and matching VHH CDR of SEQ ID NOs: 60-69 from different anti-PD-L1 antibodies that recognize different epitope on the PD-L1 and having different affinity; as well as comprising up to 3 modifications in the claimed VHH CDRs of SEQ ID NOs: 60-69.
Claim 11 encompasses broad genus of bispecific anti-TGF-β, GARP and GARP-TGF-β antibodies as recited in claim 1 and broad genus of anti-PD-L1 single-domain antibodies comprising up to 3 amino acid modifications in the VHH CDRs of SEQ ID NO: 60-69; as well as up to 15% variations the VHH of SEQ ID NOs: 82-91.
Claim 18 encompasses a broad genus of bispecific anti-TGF-β, GARP and GARP-TGF-β antibodies comprising mixing and matching different heavy chains and light chains CDRs of SEQ ID NOs:1-35 (m212, m305, m107, m202, m301, m109) of different antibodies that binds different epitope and different target antigens of TGF-β, GARP and GARP-TGF-β; and broad genus of anti-PD-L1 antibodies comprising mixing and matching VHH CDRs of different anti-PD-L1 single-domain antibodies of SEQ ID NOs: 60-69 (VHH antibody A-E).
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 TGF-β, GARP or GARP-TGF-β and PD-L1 and preventing and/or treating a disease including cancer and autoimmune diseases. 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.
The specification at [0112] discloses 5 positive anti-PD-L1 clones with high expression were obtained and designated antibody A-antibody E. The amino acid sequence of antibody A is set forth in SEQ ID NO: 82; the amino acid sequence of antibody B is set forth in SEQ ID NO: 83; the amino acid sequence of antibody C is set forth in SEQ ID NO: 84; the amino acid sequence of antibody D is set forth in SEQ ID NO: 85; the amino acid sequence of antibody E is set forth in SEQ ID NO: 86. Humanized antibodies are antibody Ahu, the amino acid sequence of which is set forth in SEQ ID NO: 87; antibody Bhu, the amino acid sequence of which is set forth in SEQ ID NO: 88; antibody Chu, the amino acid sequence of which is set forth in SEQ ID NO: 89; antibody D1hu, the amino acid sequence of which is set forth in SEQ ID NO: 90; antibody D2hu, the amino acid sequence of which is set forth in SEQ ID NO: 91.
Table 12 and Fig. 8 show that the b202-hu-H-D2hu, m202-hu +D2hu, b301-hu-H-D2hu, m301-hu and m302-hu all exhibited anti-tumor effects and that the tumor size and volume were inhibited, for example, the tumor growth inhibition (TGI) results are between 45% and 60%. Moreover, the BsAbs exhibited significantly better anti-tumor effects than the mAbs and can achieve a tumor growth inhibition of 75% or above [0178].
Table 1 and FIG. 5 shows antibody m212, antibody m305, antibody m107, antibody m202, antibody m301, and antibody m109 can all bind to GARP-TGF-β complex [0122].
Table 2 shows that antibody m212, antibody m305, and antibody m107 can all specifically bind to GARP protein [0124] .
The experimental results show that antibody m107, antibody m202, antibody m301, and antibody m109 can all specifically bind to TGF-β [0126].
[0129] As can be seen from FIG. 7, taking antibody m202, antibody m301, antibody m109, and antibody m107 as examples, these antibodies can all inhibit or neutralize TGF-β produced by Tregs.
The claim 1 is directed to a broad genus of antigen-binding moiety capable of binding to PD-L1. Claim 6 is directed to a genus of single-domain antibodies. Claims 7 and 18 encompass single-domain anti-PD-L1 nanobodies comprising mixing and matching VHH CDRs from different clones, further, claim 7 comprising mixing and matching VHH CDRs comprising up to three amino acid modification in each and every CDRs. Claim 11 is directed to up to 20% variation in the CDRs of VHH of SEQ ID NOs: 82-91.
The USPTO has released a Memo on the Clarification of Written Description Guidance For Claims Drawn to Antibodies and Status of 2008 Training Materials, 02/22/2018.
See https://www.uspto.gov/sites/default/files/documents/amgen_22feb2018.pdf.
The Memo clarifies the applicability of USPTO guidance regarding the written description requirement of 35 U.S.C. § 112(a) concerning the written description requirement for claims drawn to antibodies, including the following.
“In view of the Amgen decision, adequate written description of a newly characterized antigen alone should not be considered adequate written description of a claimed antibody to that newly characterized antigen, even when preparation of such an antibody is routine and conventional”.
In contrast to applicant’s reliance of describe the epitope of the PD-L1 in providing a fully characterized antigen / specific epitope as well as claiming structural elements of the antigen and binding affinity, there is insufficient written description of the required kind of structure-identifying information about the corresponding makeup of the claimed anti-PD-L1 antibodies/nanobodies to demonstrate possession. Also, see Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017).
There is no evidence that knowledge of the chemical structure of an antigen gives the required kind of structure identifying information about the corresponding antibodies Applicants attempt to describe the invention by describing something that is not the invention: viz., the antigens to which the antibodies may bind. There nothing in the disclosure that describes the antibodies as required by the test set forth in Ariad.
However, the anti-PD-L1 antibodies/nanobodies are required to practice the invention. The specification also fails to provide any specific structural or physical information so as to define a genus of antibodies having the desired therapeutic properties. Applicant is merely relying on the identification of integrin αvß6 as the antigen and the well-known structure of antibodies in general. However, the claims do not recite a general antibody, but an antibody having a specific desired activity. However, Federal Circuit clarification of the law of written description as it applies to antibodies. Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017).
The claims are directed to a genus of anti-PD-L1 antibodies/nanobodies. However, Federal Circuit clarification of the law of written description as it applies to antibodies. The U.S. Court of Appeals for the Federal Circuit (Federal Circuit) decided Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), which concerned adequate written description for claims drawn to antibodies. The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. § 112(a) requires adequate written description of the antibody itself. Amgen, 872 F.3d at 1378-79. The Amgen court expressly stated that the so-called "newly characterized antigen" test, which had been based on an example in USPTO-issued training materials and was noted in dicta in several earlier Federal Circuit decisions, should not be used in determining whether there is adequate written description under 35 U.S.C. § 112(a) for a claim drawn to an antibody. Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the court also stressed that the "newly characterized antigen" test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 F.3d at 1378-79, quoting Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1345 (Fed. Cir. 2010). In view of the Amgen decision, adequate written description of a newly characterized antigen alone should not be considered adequate written description of a claimed antibody to that newly characterized antigen, even when preparation of such an antibody is routine and conventional.
Moreover, there is insufficient written description of the required kind of structure-identifying information about the corresponding makeup of the claimed anti-PD-L1 antibodies/nanobodies to demonstrate possession. Also, see Amgen Inc. v. Sanofi, Aventisub LLC, No. 2017-1480 (Fed. Cir. 2017). The Court reiterated that adequate written description must “contain enough information about the actual makeup of the claimed products . . . .” The Court simultaneously suggested that the “newly characterized antigen” test “flouts” section 112 because it “allows patentees to claim antibodies by describing something that is not the invention, i.e. the antigen.” The Court concluded that for written description of an antibody to be adequate when presented with “functional” terminology, there must be an established correlation in the art between structure and function.
For instance, citing to Centocor, the Court analogized an antigen and antibody to a lock and a key. For an antigen where there is only a finite number of binding antibodies, discovering those antibodies may be routine and conventional, and description of the antigen alone may be sufficient. By contrast, for antigens with millions of keys, or millions of potentially binding antibodies, description of the antigen and even a couple of examples may be far from sufficient.
The specification discloses only 5 species (nanobodies A-E while only 4 are claimed) within the instant claim scope. The instant application encompasses (but does not exemplify) single-domain anti-PD-L1 nanobodies comprising up to 3 amino acid modification (deletion/ addition/ substitution) to the claimed HCDRs of SEQ ID NOs: 60-69 as well as up to 20% variation in the VHH of SEQ ID NO: 82-91. 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 A with another CDR from nanobody B-E 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 A-E 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 Ahu-D2hu. Ahu-D2hu comprises the whole set of the 3 CDRs of the nanobodies A-E, respectively.
With respect to the recitation a nanobody which does not comprise all 3 CDRs of the nanobody A-E, 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.
With respect to the claimed genus of anti-TGF-β, GARP and/or GARP-TGF-β antibodies.
The specification discloses only 6 species ((m212, m305, m107, m202, m301, m109 or humanized version thereof)) within the instant claim scope. The instant application encompasses (but does not exemplify) anti-TGF-β, GARP and/or GARP-TGF-β antibodies comprising up to 2 amino acid modification (deletion/ addition/ substitution) to the claimed H/LCDRs of SEQ ID NOs: 1-35 as well as up to 20% variation in the VH/VLof SEQ ID NO: 36-59. There is no teaching identifying what amino acids can be varied within the VH/VL-CDRs antiobody regions and still retain antibody or fragments capable of binding TGF-β, GARP and GARP-TGF-β. 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 TGF-β, GARP and/or GARP-TGF-β 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 H/LCDRs of the VH of different antibodies would result in antigen binding. The prior art does not support a definition of an antibody structure by mixing and matching the H/LCDR1-3 sequence of a VH and VL would result in functional anti- TGF-β, GARP and/or GARP-TGF-β antibody. The specification fails to show that all H/LCDR1, H/LCDR2, H/LCDR3 of the anti- TGF-β, GARP and/or GARP-TGF-β antibodies are equivalent and therefore interchangeable. The specification fails to establish that by replacing at least one CDR of nanobody m212 with another CDR from nanobody m305, m107, m202, m301, m109 maintains TGF-β, GARP and/or GARP-TGF-β binding. Mixing and matching different CDRs from different anti-TGF-β, GARP and/or GARP-TGF-β antibodies has not been shown to lead to TGF-β, GARP and/or GARP-TGF-β binding. Such teachings were not made part of the specification at the time the invention was made.
It is unlikely that antibodies as defined by the claims which may contain less than the full complement of CDRs from the heavy variable regions of the antibody m212, m305, m107, m202, m301, m109 fused to framework sequence, have the required binding function. The specification provides no direction or guidance regarding how to produce antibodies 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 antibody can be obtained by replacing the CDR regions of an acceptor antibody with the less than all the 6 CDRs sequences of a donor antibody as is evidenced by the humanized nanobodies hu212 comprises the whole set of the 6 CDRs of the antibodies m212, respectively.
With respect to the recitation a nanobody which does not comprise all 6 CDRs of the antibody m212, m305, m107, m202, m301, m109, 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.
7. Claim 40 is 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 colon cancer comprising administering bispecific anti-TGF-β, GARP and/or GARP-TGF-β and anti-PD-L1 nanobody recited in claim 19, does not reasonably provide enablement for a method for preventing and/or treating a disease, comprising: administering to a subject in need thereof an effective amount the monoclonal antibody or the antigen-binding fragment according to claim 26, or a bispecific antibody comprising the monoclonal antibody or the antigen-binding fragment as a first antigen-binding moiety and a second antigen- binding moiety capable of binding to PD-L1, or a pharmaceutical composition comprising the monoclonal antibody or the antigen-binding fragment or the bispecific antibody, or an antibody conjugate comprising the monoclonal antibody or the antigen-binding fragment or the bispecific antibody.; and optionally, the disease is selected from cancer or an autoimmune disease. 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.
Claim 40 encompasses a broad genus of method of treating/preventing each and every disease with the claimed anti-PD-L1 nanobody and/or anti-TGF-β, GARP and/or GARP-TGF-β antibody.
Besides, colon cancer, any treatment using the anti-PD-L1 nanobody and/or anti-TGF-β, GARP and/or GARP-TGF-β antibody 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 specification under example 10 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 specification at page 54 on Table 12 and Fig. 8 show that the b202-hu-H-D2hu, m202-hu +D2hu, b301-hu-H-D2hu, m301-hu and m302-hu all exhibited anti-tumor effects on colon cancer and that the tumor size and volume were inhibited, for example, the tumor growth inhibition (TGI) results are between 45% and 60%. Moreover, the BsAbs exhibited significantly better anti-tumor effects than the mAbs and can achieve a tumor growth inhibition of 75% or above [0178].
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 and/or anti-TGF-β, GARP and/or GARP-TGF-β antibody are lacked in the instant specification. No working empirical data demonstrating the effect of anti-PD-L1 nanobody and/or anti-TGF-β, GARP and/or GARP-TGF-β antibody would treat each and every disease. The skill in the art would doubt that the claimed administration of anti-PD-L1 nanobody and/or anti-TGF-β, GARP and/or GARP-TGF-β antibody would treat each and every disease including cancer or an autoimmune disease.
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 bispecific anti-PD-L1 nanobody and/or anti-TGF-β, GARP and/or GARP-TGF-β antibody
in preventing a disease state including cancer and autoimmune diseases. For example, the specification discloses that the experimental mice with MC-38-hPD-L1 KL3# were injected intraperitoneal (i.p.) with b202-hu-H-D2hu, m202-hu +D2hu, b301-hu-H-D2hu, m301-hu and m302-hu. (e.g. see page 54/example 10 of the instant specification). The specification does not show that b202-hu-H-D2hu, m202-hu +D2hu, b301-hu-H-D2hu, m301-hu and m302-hu being injected prior to the colon cancer establishment. Therefore, the specification at most discloses a method of treating colon cancer by administering b202-hu-H-D2hu, m202-hu +D2hu, b301-hu-H-D2hu, m301-hu and m302-hu 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.
8. Claims 19 and 20 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
9. The art made of record and not relied upon is considered pertinent to applicant's disclosure:
(i) US20240327518A1
The `518 publication teaches and claims the claimed anti-PD-L1 nanobodies comprising the claimed SEQ ID NO: 60-69, 82-91.
(ii) Yi et al. The construction, expression, and enhanced anti-tumor activity of YM101: a bispecific antibody simultaneously targeting TGF-β and PD-L1. J Hematol Oncol. 2021 Feb 16;14:27.
Yi et al. demonstrated that YM101 could simultaneously block TGF-β and PD-L1 pathways and had a superior anti-tumor effect compared to the monotherapies.
10. 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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July 15, 2026
/MAHER M HADDAD/ Primary Examiner, Art Unit 1644
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