18 Jun
2021

Patent Examination Guidelines – inventive step of a monoclonal antibody

In biopharmaceuticals, an antibody patent is one of the most valuable patents in the field. A claimed monoclonal antibody (see Table 1) can be defined as:

  • an antigen or an epitope on an antigen to which the antibody is directed;
  • a hybridoma producing the antibody; or
  • amino acid sequences constituting the antibody.

Table 1. US Hatch-Waxman system compared to Taiwan’s patent linkage system

Types of definitionStyles of claim
An antigen or an epitope on an antigen to which the antibody is directed.A monoclonal antibody that specifically binds to […] an antigen A […].

A monoclonal antibody that specifically binds to […] an epitope X on an antigen A […].

A hybridoma producing the antibody.A monoclonal antibody against an antigen A that is produced by a hybridoma deposited as […].
Amino acid sequences constituting the antibody.A monoclonal antibody against an antigen A that comprises:
  • a heavy chain variable region as set out in SEQ ID NO […]; and
  • a light chain variable region as out in SEQ ID NO […].

A monoclonal antibody against an antigen A that comprises:

  • a heavy chain variable region comprising:
    • VHCDR1 as set out in SEQ ID NO […];
    • VHCDR2 as set out in SEQ ID NO […]; and
    • VHCDR3 as set out in SEQ ID NO […]; and
  • a light chain variable region comprising:
    • VLCDR1 as set out in SEQ ID NO […];
    • VLCDR2 as set out in SEQ ID NO […]; and
    • VLCDR3 as set out in SEQ ID NO […].

It is preferable if the antigen to be directed by the claimed antibody is a novel and inventive one. If it is novel and inventive, a monoclonal antibody patent can be defined directly by the antigen and a patent claim with the broadest scope can be granted. If it is not novel and inventive, although an antibody can still be claimed by a hybridoma producing the antibody or amino acid sequences constituting the antibody, it will be unclear whether such a defined antibody can be considered to be inventive enough (see Table 2).

Table 2. Claiming a monoclonal antibody when an antigen to be directed by the antibody is known or obvious

Antibodies in the prior art documentThe monoclonal antibody to be claimed
A monoclonal antibody that specifically binds to […] an antigen A […]. 
A monoclonal antibody that specifically binds to […] an epitope X on an antigen A […].A monoclonal antibody that specifically binds to […] an epitope Y on an antigen A […].
A monoclonal antibody against an antigen A that is produced by a hybridoma α […].A monoclonal antibody against an antigen A that is produced by a hybridoma β […].
A monoclonal antibody against an antigen A that comprises:
  • a heavy chain variable region as set out in SEQ ID NO: 1; and
  • a light chain variable region as set out in SEQ ID NO: 2.
A monoclonal antibody against an antigen A that comprises:
  • a heavy chain variable region as set out in SEQ ID NO: I; and
  • a light chain variable region as set out in SEQ ID NO: II.

A monoclonal antibody against an antigen A that comprises: a heavy chain variable region comprising:

    • VHCDR1 as set out in SEQ ID NO: 3;
    • VHCDR2 as set out in SEQ ID NO: 4; and
    • VHCDR3 as set out in SEQ ID NO: 5; and
  • a light chain variable region comprising:
    • VLCDR1 as set out in SEQ ID NO: 6;
    • VLCDR2 as set out in SEQ ID NO: 7; and
    • VLCDR3 as set out in SEQ ID NO: 8.
A monoclonal antibody against an antigen A that comprises:
  • a heavy chain variable region comprising:
    • VHCDR1 as set out in SEQ ID NO: III;
    • VHCDR2 as set out in SEQ ID NO: IV; and
    • VHCDR3 as set out in SEQ ID NO: V; and
  • a light chain variable region comprising:
    • VLCDR1 as set out in SEQ ID NO: VI;
    • VLCDR2 as set out in SEQ ID NO: VII; and
    • VLCDR3 as set out in SEQ ID NO: VIII.

The biotech section of the Patent Examination Guidelines regarding patentability of a monoclonal antibody was amended in 2020 (see Table 3). The amendment entered into effect on 15 January 2021.

Table 3. Recent amendment to Part II of the Patent Examination Guidelines, Section 9.4.2(5), Chapter 10

BeforeAfter (changes marked in italics)

If an antigen is known and it is clearly known that the antigen has immunogenicity (for example, said antigen clearly has immunogenicity because a polyclonal antibody of the antigen is known or the antigen is a polypeptide with a large molecular weight), the invention of a monoclonal antibody of the antigen does not involve an inventive step. However, if the invention is further defined by other features, and hence has unexpected technical effects, the invention of that monoclonal antibody involves an inventive step.

If an antigen is known, a monoclonal antibody against the antigen characterised by structural features is obviously different from a known monoclonal antibody in the key sequence that determines its function and use, and the prior art does not provide technical motivation to obtain the monoclonal antibody having the above sequence, and the monoclonal antibody can produce beneficial technical effect(s), then the invention of the monoclonal antibody involves an inventive step. If an antigen is known and it is clearly known that the antigen has immunogenicity (for example, said antigen clearly has immunogenicity because a polyclonal antibody of the antigen is known or the antigen is a polypeptide with a large molecular weight), the invention of a monoclonal antibody defined only with the antigen does not involve an inventive step. However, if the invention is further defined by a hybridoma that secretes the monoclonal antibody against the antigen, and hence has unexpected technical effects, the invention of that monoclonal antibody involves an inventive step.

Before the amendment to Part II of the Patent Examination Guidelines, Section 9.4.2(5), Chapter 10, even with totally new complementarity-determining regions (CDRs) directed to a known antigen, a monoclonal antibody could hardly be considered inventive unless that new antibody had unexpected technical effects when compared to a Chinese prior art antibody directed at the same antigen. In fact, similar obstacles for claiming new monoclonal antibodies are also present in the patent practices of many other countries (eg, the United States, Japan and a number of countries in Europe).

For the patentability of a novel monoclonal antibody, the previous regime in China, or the current regime in many other countries, is reasonable to a certain degree, because a skilled artisan can, through a conventional method, readily produce a new antibody with new CDR sequences based on a known antigen (see Figure 1).

Figure 1. A conventional method for producing a monoclonal antibody

However, problems have come up as a result of this regime.

The first problem is that a comparison of technical effects between the claimed antibody and a prior art antibody directed at the same antigen cannot always be carried out, especially when the reference documents cited by the examiner have mentioned only generally, and not specifically, the prior art antibody. This means that it is not easy or even possible for the applicant to obtain the prior art antibody for comparison.

The second problem is that it is still difficult to select, from multiple antibodies produced through a conventional method, an antibody that has a property comparable with that of a prior art antibody. There are dissenting voices regarding the fairness of rejecting an antibody with a totally new and unobvious CDR sequence. It lacks inventive step because it is directed at a known antigen and fails to attain a significantly higher antibody effect. One of the reasons for this is that an antibody with unobvious CDR sequences and comparable effects could be inventive because it meets the provision in the Patent Examination Guidelines that: “an invention shall be regarded as producing advantageous technical effects and therefore representing notable progress in any of the following circumstances… where the technical solution provided by the invention is of a different inventive concept and can produce a technical effect of substantially the same level as in the prior art.”

Another reason is that an antibody with unobvious CDR sequences and comparable effects could involve an inventive step because it seems to meet the standard of inventive step of chemical compounds, where a compound with a totally new and unobvious structure, and a certain use or effect, does involve an inventive step.

Fortunately, after the amendment to the guidelines, a new monoclonal antibody directed at a known antigen will be acknowledged as sufficiently inventive as long as it has new and unobvious CDR sequences while producing beneficial technical effects without any necessarily unexpected effects (eg, a significantly higher specificity or affinity to the known antigen than a prior art antibody directed at the same antigen). In other words, a threshold for patentability of a novel monoclonal antibody is considerably lowered in China.

With regard to this change, the China National Intellectual Property Administration would like to resolve the problems of the previous regulations, in particular to adapt the regulations to focus on unobvious structures of claimed novel antibodies, which seems more reasonable. However, there may be another deeper reason contributing to this rule change that aims to encourage investment and innovation in the antibody industry. Although there seems to be no official explanation for any motivation regarding this amendment, the statistics in Figures 2 to 5 may offer a possible illustration.

Figure 2. Number of patent applications and granted patents claiming monoclonal antibodies in China

Figure 3. Number of patent applications and granted patents claiming monoclonal antibodies in the United States

Figure 4. Number of patent applications and granted patents claiming monoclonal antibodies in Europe

Figure 5. Number of patent applications and granted patents claiming monoclonal antibodies in Japan

As can be seen in Figure 2, the number of granted patents claiming monoclonal antibodies is much less than that of patent applications claiming monoclonal antibodies for at least 20 years. Moreover, the ratio of the number of granted patents to that of the patent applications claiming monoclonal antibodies per year decreased sharply after 2014 and 2015.

Creating inventive works in the field of monoclonal antibodies is becoming increasingly difficult across the world. The financial rewards from owning patent rights cannot sustain continuous research and development of new antibody medicaments. However, changes to the Patent Examination Guidelines could be considered a first exploratory step in encouraging research and development in the field of new antibody medicaments in China. The public will benefit as a result of an increase in the choice of patent antibody medicaments with the same or similar therapeutic effects.

A new era of patent antibody medicaments is coming.