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 .
Claim Status
Amendments to the claims filed 13 Aug 2024 are acknowledged. Claims 1-53, 62, and 72-79 are canceled. Claims 54-61, 63, and 65-71 are amended. Claims 80-82 are newly added. Claims 54-61, 63-71, and 80-82 are pending and under consideration.
Claim Rejections - 35 USC § 112(a)
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.
Claims 54-61, 63-71, and 80-82 are rejected under 35 U.S.C. § 112(a) because the specification, while being enabling for
a method of assessing the pharmacokinetic properties of a drug targeting human LAG-3, the method comprising the steps of
administering the drug to a mouse whose genome comprises a humanized Lag-3 gene at an endogenous Lag-3 locus,
wherein a humanized Lag-3 polypeptide is expressed from the humanized Lag-3 gene on the surface of activated T-lymphocytes in the mouse,
wherein the humanized Lag-3 polypeptide comprises
the first two N-terminal immunoglobulin-like domains of a human LAG-3 polypeptide and
the transmembrane and intracellular domains of an endogenous mouse Lag-3 polypeptide,
and wherein the humanized Lag-3 gene is operably linked to the endogenous mouse Lag-3 promoter at the endogenous Lag-3 locus,
and performing an assay to determine one or more pharmacokinetic properties of the drug targeting human LAG-3;
does not reasonably provide enablement for performing the method in species of rodent other than mouse. Note that while the term mouse is used to describe many rodent species, the enabled scope of the claimed invention is limited to the house mouse, Mus musculus. 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/or use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). The court in Wands states, “Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word ‘undue’, not ‘experimentation.’” (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). When determining whether a specification meets the enablement requirement, some of the factors to be analyzed are: (1) the breadth of the claims, (2) the nature of the invention, (3) the state of the prior art, (4) the level of one of ordinary skill in the art, (5) the level of predictability in the art, (6) the amount of direction provided by the inventor, (7) the existence of working examples, and (8) whether the quantity of any necessary experimentation to make and use the invention based on the content of the disclosure is undue (Wands). While all of these factors are considered, those sufficient for establishing a prima facie case are discussed below.
Nature of the invention
The claims are drawn to a method of assessing pharmacokinetic properties of drugs targeting human LAG-3 using a rodent comprising a humanized Lag-3 gene expressing humanized Lag-3 protein based on replacing the extracellular domains of the endogenous rodent protein with the corresponding human domains inserted at the endogenous Lag-3 promoter under control of the endogenous Lag-3 promoter. Claims 63-71 are further drawn to performing the method of assessing in rodents comprising humanized Lag-3 and humanized Pdcd1.
Breadth of the claims
The claims are broad with respect to the species of rodent comprising humanized Lag-3 comprising humanized Lag-3 and humanized Pdcd1 in which the claimed method is performed. There are over 2200 species of rodents in the order of Rodentia, only a few of which have been used to generate transgenic animals, and thus the claims encompass numerous non-enabled embodiments.
Existence of working examples
Example 1 describes generation of a humanized Lag-3 gene comprising exons 2, 3, and 4 of human LAG-3 used to humanize the endogenous mouse Lag-3 gene (par. 204). Example 2 describes making and characterizing mice homozygous for humanized Lag3. Example 3 describes assays to screen Lag-3 and PD-1 antibodies in mice homozygous for humanized Lag-3 and homozygous for humanized Pdcd1. No working examples are provided for humanization of endogenous Lag-3 or Pdcd1 for species of rodent other than mouse.
Amount of direction provided by the inventor
The specification provides that in some embodiments, the rodent may be from the superfamilies Dipodoidea or Muroidea, the families Calomyscidae, Cricetidae, Muridae, Nesomyidae, Platacanthomydiae, and Spalacidae, or may be a mouse or rat (par. 91). The specification further provides for how to produce a non-human animal having a humanized Lag-3 gene (par. 122-167). However, description of how to make such animals is contemplated at a high level of generality and does not include detail for how to adapt the invention to different species of rodent.
State of the prior art, Level of one of ordinary skill in the art, and Level of predictability in the art
As of the earliest effective filing date of the present application, 20 Nov 2015, the art is free of a rodent comprising the humanized Lag-3 gene and free of a rodent comprising the humanized Lag-3 gene and humanized Pdcd1 as claimed. Therefore, guidance is unavailable from the art regarding making the specific transgenic animals required to perform the assay. In absence of specific guidance for making a transgenic rodent comprising humanized Lag-3, a skilled artisan may rely on general guidance for making and using transgenic rodents generally. This art regards the practice of making transgenic animals as highly unpredictable.
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. In re Soll, 97 F.2d 623, 624, 38 USPQ 189, 191 (CCPA 1938). In cases involving unpredictable factors, such as most chemical reactions and physiological activity, more may be required. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). See MPEP § 2164.03.
Scheer (N. Scheer, et al., Drug Discov Today, 2013) teaches mice are the most common used mammalian organism for studying human physiology and disease (Introduction p. 1200). Scheer further teaches that generation of humanized mice requires advice from experts because of the technical skills required and because "even with a well-designed strategy the accurate expression profile of the human transgene and its functioning in a mouse context cannot be ensured" (Concluding Remarks pp. 1208-1209). Thus, the level of skill required to make a humanized mouse such as the ones used in the claimed invention requires a very high level of skill even compared to other parts of the biological arts and the level of unpredictability in the art of making humanized mice is very high. Furthermore, these challenges exist when using mice for biological research, which are commonly used and generally well understood. A skilled artisan would expect greater challenges
Jackson (R.K. Jackson, ILAR Journal, 1997) teaches that mice, rats, guinea pigs, and hamsters "account for the majority of rodents used in biomedical research" and notes that other species of rodents are rarely used and considered unusual species. Li (S. Li, et al. Cell Rep, 2023) teaches that, even well after the earliest effective filing date of the present invention, genome editing is challenging in non-traditional model species due to the taxonomic diversity of rodent species (Introduction p. 1). Li further teaches that, at the time of earliest effective filing date of the present invention, generation of transgenic mammals required ex vivo gene editing, which has the following drawbacks:
"(1) it uses specialized microinjection or electroporation equipment; (2) it needs to be performed by highly skilled personnel because it is technically challenging; (3) it requires a deep knowledge of the reproductive physiology of the species in question because it relies on hormonal cocktails that need to be customized; (4) vasectomized males have to be surgically prepared, which, together with the need for having pseudo-pregnant females, increases the number of animals needed for each experiment and complicates logistics; (5) it requires embryo transfer, which typically involves a surgical [procedure] on the recipient animal; and (6) the need for manipulating zygotes restricts genome editing to a small group of species for which early embryo isolation, culture, and manipulation have been optimized." (Introduction p. 1).
Thus, Li teaches that generation of transgenic animals requires a very high level of skill not accessible to the ordinary skilled artisan and is unpredictable when applied to new species.
Conclusions
The specification and the prior art provide working examples that narrowly enabling for the invention as claimed. However, the breadth of the claims encompasses numerous non-enabled embodiments and neither the specification nor the prior art provide sufficient direction for a skilled artisan to make and/or use the full scope of the claimed invention. The art teaches that the creation of new transgenic animals is unpredictable and requires a high level of specialized skill not held by the ordinary skilled artisan. The art further teaches that use of rodents to generate transgenic animals is limited to a small number of species that gene editing in rodents not traditionally used in laboratory research is difficult and unpredictable. Therefore, a skilled artisan would have to overcome barriers in the art to creating new genetic constructs and transgenic animals, representing an undue burden of experimentation to make and use the full scope of the claimed invention.
Conclusion
No claim is allowed.
Claims 54-61, 63-71, and 80-82 contain subject matter that is free of the prior art. A mouse comprising humanized Lag-3 as described in claim 54 is not found in the art as of the earliest effective filing date, 20 Nov 2015, and therefore, methods of using said mouse or a mouse further comprising humanized Pdcd1 to assess pharmacokinetic properties of a drug targeting human LAG-3 are also free of the prior art.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Eric B Wright whose telephone number is (571) 272-2607. The examiner can normally be reached Mo - Fr, 09:00 a.m. - 05:00 p.m. Eastern. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Peter Paras can be reached at (571) 272-4517.
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Eric B Wright, PhD
Examiner
Art Unit 1632
/Eric B Wright/Examiner, Art Unit 1632 /VALARIE E BERTOGLIO/Primary Examiner, Art Unit 1632
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